Hybrid Lymphatic Drug Delivery Vehicles as a New Avenue for Targeted Therapy: Lymphatic Trafficking, Applications, Challenges, and Future Horizons

Abstract

Lymphatic drug targeting is an effective approach for targeting immunomodulators, and chemotherapeutic drugs at a specific organ or cellular location. The cellular, paracellular, and dendritic cell trafficking machinery are involved in the lymphatic transport of therapeutic agents. The engineering of triggered and hybrid lymphatic drug delivery systems (LDDS) is a promising strategy to fight cancer metastasis and microbial pandemics. Hybrid lymphatic drug delivery systems can be tailored and developed by grafting the conventional LDDS with biological agents. Thus, hybrid LDDS could collect the benefits of conventional and biological delivery systems. Moreover, the fabrication of triggered LDDS increases drug accumulation in the lymphatic system in the response to an internal stimulus such as pH, and redox status or external such as magnetic field, temperature, and light. Stimuli-responsive LDD systems prevent premature release of payload and mediate selective drug biodistribution. This improves therapeutic impact and reduces the systemic side effect of anticancer, immunomodulatory, and antimicrobial therapeutics. This review highlights the challenges and future horizons of nanoscaled-triggered LDDS and their influence on the lymphatic trafficking of therapeutic molecules.

Graphical abstract

Introduction

Physiologically, the lymphatic system (LS) is a vital organ in the human body, it cooperated with the cardiovascular, immune system and digestive systems for the maintenance of homeostasis (O'Melia et al. 2019). Moreover, LS has an essential role in the defense against external invaders, and intestinal absorption of lipids, lipophilic medicines, and macromolecule therapeutics (O'Melia et al. 2019). The lymphatic endothelial cells (LEC) gap is about 30–120 nm. In this regard, the particles, macromolecules, and lipophilic drugs are transported into systemic circulation through the LS gateway (Cense et al. 2006; Franco et al. 2020). By contrast, under pathological conditions, the LEC gap become (300–500 nm), therefore, the LS has a major role in inflammatory diseases such as rheumatoid arthritis, systemic lupus, and scleroderma. Furthermore, LS dysfunction is associated with ascites, malnutrition, and obesity (Bora et al. 2017). Likewise, filariasis, and tuberculosis, as well as viral infection such as human immune deficiency virus (HIV), other viral invasions, autoimmune diseases, rejection of organ transplants, and atopic dermatitis, takes place through the LS (Trevaskis et al. 2015). Consequently, the LS can be considered a potential target for drug delivery to achieve the optimum therapeutic effect. Specifically, orally administered lipid-based delivery systems stimulate chylomicron biosynthesis as cargoes lymphatic delivery (Zhang et al. 2021; Satapathy and Patro 2021; Ryšánek et al. 2020).

Predominantly, the LS plays a vital role in cancer metastasis, however, the tumor cells are traveling in the lymphatic vessels to invade the other organs (Leong and Witte 2022). In this respect, LS is the road to lung, breast, melanoma, prostate cancer, and other cancers metastasis (Leong and Zager 2022). Particularly, the tumor microenvironment is associated with the formation of leaky lymphatic vessels with openings of 500 nm, this enhances tumor cell migration (Zhang and Lu 2014). Furthermore, the tumor cells secrete the protease enzymes that degrade the extracellular matrix (ECM) resulting in the disorganization of the cells, metastasis, and invasion of other tissues (Guan 2015). Besides, tumor cells liberate extracellular vehicles (EVs) such as exosomes, oncosomes, and other EVs that carry mediators involved in cancer development, and lymphatic cancer metastasis (Minciacchi et al. 2015; Nicolini et al. 2021). Specifically, oncosomes have cellular, and organ tropism, and are associated with lymphatic cancer metastasis (Leong and Zager 2022). Therefore, EVs are suggested as prospective lymphatic drug delivery systems (LDDS) to improve the therapeutic outcomes of anticancer agents and control cancer metastasis (Leong and Zager 2022). Taken together, the LS is the main channel for cancer metastasis of cancer cells (Franco et al. 2020). Moreover, the LS collaborated with the immune system by mobilizing antigen-presenting cells against invading pathogens (Singh et al. 2014b). particularly, the lymphatic vessels are necessary for dendritic cell migration, the transport pathway for T and B lymphocytes into the lymph node as critical features of an efficient adaptive immune response (Singh et al. 2014b). In this context, the LDD is urgently required to deliver medicines to lymph nodes to fight cancer metastasis (Khan et al. 2013).

Taken together, lymphatic drug delivery (LDD) could provide an effective tactic for the targeting of anticancer and immunomodulatory agents to a specific destination (Khan et al. 2013). LDDS could localize the drugs into LS by intra-luminal, intravascular, intra-lymphatic, and intra-tissue routes (Zhang et al. 2021; Khan et al. 2013). Consequently, LDD is exploited as an effective approach for the delivery and targeting of immunomodulatory agents, anti-infective agents, and chemotherapeutic drugs into the LS (Franco et al. 2020). Exactly, LDDS could increase the accumulation of the drug in the lymph node (Khan et al. 2013). Ample approaches including the synthesis of prodrugs, the activating of chylomicron biosynthesis, and the fabrication of nanocarriers facilitate LDD (Zhang et al. 2021; Satapathy and Patro 2021; Ryšánek et al. 2020). Predominantly LDD depends on the lipophilicity of the drugs, particle size, and surface charge of LDDS. These factors should be considered during the development of nanomaterials used for LDD (Trevaskis et al. 2015). Figure 1, shows the principles, and approaches of LDD, as well as the drugs used for lymphatic delivery.

Fig. 1.

Principles, approaches, and drugs of lymphatic drug delivery

The leaky lymphatic capillaries play an important role in the uptake, and absorption of drugs through the lymphatic tissues (Zhang et al. 2021; Khan et al. 2013). In this regard, the prospective therapeutic agents can be loaded into conventional LDDS such as lipid nanocarriers, nanoparticles, carbon nanotubes, micelles, polymers, or other cargoes to deliver the drug to the precise site of the LS (Manspeaker and Thomas 2020). Herein, the drugs become in contact with the tumor lesion to elicit their cytotoxic or immunomodulatory effect (Manspeaker and Thomas 2020). In this regard, the corona vaccines were developed and loaded into lipids nanoparticles (LNPs) to stimulate antibody production by the LS (He et al. 2022, Noor 2021). Pfizer and Moderna companies launched vaccines against the coronavirus that consist of mRNA loaded within LNPs (Weiss et al. 2020). Moreover, the developed LNPs were engineered with polyethylene glycol (PEG) to produce PEGylated LNPs that increase their stability during storage (Cross 2021).

Despite the success of conventional drug delivery systems to deliver therapeutic agents into the target cells, however, they still have limitations due to the presence of foreign materials (Ren et al. 2016). Therefore, nature and endogenous cargoes such as cells, EVs, lipoproteins, and other payloads are suggested as LDDS. These payloads are devoid of the limitations associated with conventional drug delivery systems (Ke and Afonin 2021). Thus, the endogenous delivery systems evade biocompatibility, immunological reactions, and overcoming the biological barrier (Ren et al. 2016). The EVs such as exosomes, oncosomes, and others are endogenous trucks of nucleic acids, peptides, proteins, lipids, and therapeutic agents (Ke and Afonin 2021). Essentially, the integration of conventional and biological drug delivery vehicles resulted in the assembly of hybrid drug delivery systems (Sherif et al. 2019).

Hybrid cargoes gather advantages over both conventional and biological cargoes. Moreover, they could deliver the medicine into the cellular and subcellular compartments of the liver, spleen, lungs, bone marrow, tumor cells, and other cells in a specific manner (Harisa and Faris 2019; Harisa et al. 2017). Cooperatively, hybrid drug delivery cargoes are suggested to govern the advantages of conventional and biological delivery systems (Harisa and Faris 2019; Harisa et al. 2017). Moreover, hybrid cargoes can be tagged by pH, redox, temperature, and light-responsive agents consequently, the triggered and hybrid LDDS could release the payload within LS under the effect of external or internal stimuli (Kato et al. 2019). In this context, the triggered hybrid nanocarriers could be used as a platform for LDD to improve therapy and reduce systemic drug toxicity (Manspeaker and Thomas 2020; Kato et al. 2019). Accordingly, LDDS could be targeted the drugs for metastatic cancer with high uptake by the LS at low toxicity to normal cells (Singh et al. 2014a). Small molecules, nucleic acids, proteins, and peptides can be efficiently loaded into LDDS for therapeutic and imaging approaches (Manspeaker and Thomas 2020).

Taken together, hybrid LDD vehicles are prospective tools for diagnosis and increase the bioavailability and therapeutic impact of anticancer, anti-infective, and immunomodulatory agents. The hybridization of synthetic agents with biological ones can increase the impact of LDDS in biomedical applications. Therefore, this review aims to highlight the rationale and principles of LDD. Moreover, hybrid LDDS challenges and prospects were discussed.

Physiological Trafficking of Materials to the LS

The LS acts as a gateway for the absorption of lipids, long-chain fatty acids, and lipid-soluble vitamins from the intestinal tract. Moreover, LS serves as a drainage system for returning waste products, proteins, and excess fluid into the circulatory system (Bora et al. 2017). In addition, the LS plays an important role in the body’s immune system by transporting antigen-presenting cells such as dendritic cells to the lymph nodes (Vishwakarma et al. 2019). Likewise, the materials and therapeutic molecules reached the LS following parental, oral, or other routes of administration (Vishwakarma et al. 2019). Lymphatic endothelial cells have specific receptors, one layer, little junctions, more fenestrated compared to blood vessels (Trevaskis et al. 2008). Therefore, the LS facilitates intercellular signaling between the tissues and drains lymph nodes through solute transport by passive and active processes. Likewise, LS has a specific role in drug transportation (Vishwakarma et al. 2019). The transcellular, paracellular, and immune cell trafficking mechanisms are involved in lymphatic transport (Vishwakarma et al. 2019). The molecules can pass through intercellular junctions in a paracellular manner or transport across the LEC by active transport or transcytosis pathways (Trevaskis et al. 2008).

Lymphatic trafficking is a contributor to the oral bioavailability of lipophilic drugs such as testosterone derivatives, probucol, cyclosporine, retinoids, lycopene, lipophilic cannabinoids, protein, peptides, and several lipophilic prodrugs (Trevaskis et al. 2008). Lipoproteins are critical for lymphatic transport, they aid in the entry process and facilitate the movement of the payloads across the enterocytes (Trevaskis et al. 2008). In this context, the enterocyte-based biosynthesis of triglyceride-enrich lipoprotein nanoparticles mediates the transport of lipophilic drugs to the systemic circulation through the thoracic lymphatic duct (Liu et al. 2006; Stano et al. 2011). Large cargoes and macromolecule medicines use the more permeable lymphatic capillaries for absorption (Trevaskis et al. 2008). In this regard, the macromolecule drugs, peptides, proteins, and antigens crossway the epithelium and are drained into the LS (Liu et al. 2006; Stano et al. 2011).

Orally administered nanomedicines are absorbed by Peyer’s lymph node, while, subcutaneously administered ones are absorbed by the lymph nodes (Singh et al. 2014a). As well, the gut-associated lymphoid tissue that forms Peyer’s patches provides an entry point for the particles to the lymphatic circulation (Stylianopoulos et al. 2010). Additionally, the intradermal injection promotes high lymphatic uptake, due to the skin having high lymph flow rates. Herein, intramuscular or intradermal injections of drug materials in the range of 10–100 nm drive to the lymphatic vessels, however, the others less than 10 nm primarily enter blood capillaries (Stylianopoulos et al. 2010). The nasally administered nanoparticles for vaccination interact with nasal-associated lymphoid tissues and elicit protective immune responses (Stano et al. 2011).

Drugs that are lymphatically transported escape first-pass metabolism with increased drug concentration in LS. This provides an effective prospect to improve oral bioavailability and targeting of anticancer, immunomodulatory, and anti-infective agents (Brocks and Davies 2018). Herein, the therapeutic interest could target different regions of the LS at extraordinary concentrations (Liu et al. 2006; Stano et al. 2011). Moreover, lymphatic absorption donates to multiple peaking phenomena and flip-flop pharmacokinetics of orally administered drugs (Brocks and Davies 2018). Figure 2, demonstrates the lymphatic trafficking of small drugs, macromolecule therapeutics, and drug-loaded LDDS.

Fig. 2.

Schematic illustration of the machinery of lymphatic trafficking via paracellular, transcellular, and immune-cell trafficking

Transcellular Lymphatic Trafficking

The transcellular process happens through the transportation of material across the cell membrane of endothelial lymphatic cells (Vishwakarma et al. 2019). Both small molecules are large particles that could be transported through endothelial cells of lymphatic vessels within the interstitial space or basolateral space of the intestinal membrane (Trevaskis et al. 2015). However, small molecules are less prone to lymphatic delivery via transcellular trafficking. This is attributed to high blood flow that rapidly clears interstitial space from small molecules (Han et al. 2014). On contrary, the large particles could be transported through endothelial cells of lymphatic vessels to LS. This is achieved through receptor present on the surface of endothelial cells by a process known as receptor-mediated endocytosis (Vishwakarma et al. 2019).

Paracellular Lymphatic Trafficking

Paracellular transportation occurs following the passage of material between endothelial cells of lymphatic vessels (Vishwakarma et al. 2019). Similar to transcellular transportation, small molecules are less susceptible to lymphatic delivery through this mechanism as a result of the sink condition maintained with blood supply (Han et al. 2014). On the other hand, the large particles are less predisposed to blood clearance owing to the small space between endothelial cells of blood vessels. Therefore, large particles are more susceptible to lymphatic uptake through large gaps present between endothelial space of lymphatic vessels (Permana et al. 2021).

Immune-Cell Lymphatic Trafficking

Lymphatic delivery could be achieved by utilizing immune cells that have a key to access the lymphatic vessels (Vishwakarma et al. 2019). Immune cells have key access to LS through blood capillaries that supply lymph nodes with nutrients. Therefore, the fabrication of large particles with a high tendency of lymphatic uptake increases the chance of LDD following parenteral administration (Sensken et al. 2009). Alternatively, the LS could be accessed through M cells present on the payer’s patches of intestinal membrane. Fabrication of large particles with a high tendency for M cell uptake increases lymphatic delivery using enriched immune cells (Zhang et al. 2021).

Principles of LDD

Several factors should be considered during the selection and preparation of nanoparticles used for LDD. These factors are including lipophilicity, particle size, and surface charge (Trevaskis et al. 2015).

Lipophilicity of Therapeutic Agent

Based on the literature, the log P value is the most predominant factor for the susceptibility of administered therapeutic agents to lymphatic transport following oral administration (Zhang et al. 2021). Administered therapeutic molecules with a log P value of more than 5 are usually absorbed and transported through LS as a result of low solubility within aqueous hydrophilic blood (Elz et al. 2021). Consequently, enhanced LDD of therapeutic hydrophilic molecules could be achieved via prodrug approaches. This achieved conjugation of hydrophobic moiety with the hydrophilic function group in the therapeutic molecule (Han et al. 2021).

The Particle Size of LDDS

Conventional administration of therapeutic molecules via intravenous or interstitial injection failed to attain therapeutic level unless using a highly toxic dose. This is attributed to the rapid washing of therapeutic molecules from interstitial space via rapid blood flow (Trac and Chung 2021). Therefore, therapeutic molecules are usually loaded within nanosystems to enhance LDD where their particle size plays a crucial role in LDD (Punjabi et al. 2021). This is achieved via the inherent transportation of nanoparticles between large fenestrations present in the lymphatic vessels (De Oliveira et al. 2022). The nanosystems are predisposed to LDD following opsonization by immune cells (Bednarczyk et al. 2021).

Regarding oral administration, small hydrophobic molecules could be absorbed and transported through portal veins even with minimal drug solubility owing to physiological sink conditions (Zhang et al. 2021). This is attributed to their ability to pass through small japs between endothelial cells of portal veins (Rizk et al. 2021). Thus, conjugation or loading therapeutic molecules with macromolecules or nanoparticles could enhance their LDD (Kobayashi et al. 2014). Even though increasing the particle size of nanocarriers above 10 nm improves the opportunity for LDD, the size should not exceed 500 nm (Sharma et al. 2016). This could be beneficial in the case of drug-susceptible for gastric and enzymatic degradation that increases the drug available for the absorption process (de Souza et al. 2022).

Surface Charge of LDDS

The surface charge of the LDDS is dictated by the zeta potential (ZP), ZP of -30 mV indicates a strongly anionic nature, and values between + 10 and − 10 mV indicate neutral behavior and values. + 30 mV indicates a cationic nature (Khan et al. 2013). Despite, cationic-charged particles having high cellular uptake, the negatively charged particles are vulnerable to lymphatic delivery via M cells (Sharma et al. 2016). Neutral and negatively charged absorbed particles have a high tendency to stay longer in the body (Bahmani et al. 2018). In agreement with such a hypothesis, Pramanik and Thakkar prepared a lipid-based formulation to enhance the LDD of Tizanidine (Pramanik and Thakkar 2020). Furthermore, it was reported that the negatively charged liposomes showed improved lymphatic uptake compared with the positively charged liposomes (Khan et al. 2013). Another study observed the order of liposomal uptake by the lymph nodes ordered as follows: negative, positive, and neutral charge (Khan et al. 2013).

Type LDD

Both passive, and active targeting mechanisms are involved in the entry of LDDS into the tumor cells. Moreover, the triggered LDD could be utilized to avoid premature drug release from the nanocarriers before it reaches the main site of action (Mahmoud et al. 2022). Figure 3, indicates the type of LDD in terms of passive, active, and triggered LDD.

Fig. 3.

Classification and examples of lymphatic drug delivery types including passive, active, and triggered mechanisms

Passive LDD

Generally, in tumor passive targeting machinery, the transport of cargoes is achieved by leaky tumor vasculature into the tumor cell by passive diffusion mechanism (Pirollo and Chang 2008). Then the drug is accumulated at the target site by the enhanced permeation and retention (EPR) effect noticeable process in cancer targeting (Sherif et al. 2019). Also, the EPR effect is relevant for all fast-growing solid tumors. The EPR effect is more positive when the nanocarriers can escape immune surveillance and circulate for a long time (Pirollo and Chang 2008). Passive targeting is limited by the degree of tumor vascularization and angiogenesis. Moreover, the large and long-circulating carriers are retained in the tumor cell for a longer period, however, smaller molecules are liberated from the cancer cells (Danhier et al. 2010).

Additionally, in the passive LD targeting mechanism, the cargo uses the landscape of the lymph system for transportation (Singh et al. 2014a). Generally, the transfer of particles is inversely proportional to the size. Small particles (< 100 nm) easily penetrate the microvasculature of lymphatic metastatic tumors (Singh et al. 2014a). In this context, interstitial injection and oral administration were utilized to achieve LDD (Permana et al. 2021). Interstitial administration is attained following subcutaneous, intradermal, and intramuscular injections. Large molecules are passively transported from interstitial space to lymphatic vessels through large fenestration between endothelial cells of lymphatic vessels (Trevaskis et al. 2015).

The arrival of orally administered therapeutic molecules to LS is achieved by incorporation into CMs assembled within enterocytes. Herein, the lipophilic therapeutic molecules with log P of more than 5 are passively incorporated within the hydrophobic core of CMs (Zhang et al. 2021). Then, the CMs are normally absorbed and transported through LS, afterward, the cargoes are delivered into system circulation (Ahn and Park 2016). In this regard, Caliph et al. co-administer a therapeutic molecule with a lipid vehicle to enhance LDD. In-vivo results revealed that lipid vehicle increased drug concentration in lymph fluid collected from mesenteric lymph (Caliph et al. 2000).

Active LDD

Usually, active drug targeting is achieved via biochemical interactions between the receptor on the cancer cell and the ligand-decorated drug delivery cargoes (Singh et al. 2014b). The ligand binds to a receptor overexpressed on the plasma membrane of cancer cells compared to the normal cells. These receptors include receptors of folate, transferrin, growth factor, low-density lipoproteins, and other receptors. Accordingly, ample ligands such as monoclonal antibodies, transferrin, folate, biotin, and others have been utilized to enhance LDD via the receptors overexpressed on the membrane of the target cell (Muddineti et al. 2015; Kumar et al. 2020; Nunes et al. 2017). Moreover, binding specific ligands on the surface of nanoparticles allow them to penetrate M cells through expressed receptors (Shreya et al. 2019). For example, binding mannose ligands to nanoparticles increased loaded-drug delivery to LS through mannose receptors (Pandya et al. 2021). Likewise, integrin was used as a binding ligand to enhance the LDD of orally administered therapeutic molecules through integrin receptors (Lin et al. 2019).

Additionally, the high endothelial venules (HEV) supply lymph nodes with nutrients, immune cells, and other materials. Moreover, HEV is enriched with several types of overexpressed receptors (Vella et al. 2021). Consequently, active LDD could be achieved following the administration of nanoparticles through HEV and receptor-mediated endocytosis (Trevaskis et al. 2015). In this regard, a ligand that binds to surface receptors on HEV might be expected to enhance the active uptake. The hyaluronic acid receptor is responsible for the uptake of lipoproteins particles tagged with hyaluronic acid into LS (Saha and Rai 2021)., Yang et al. prepared nanoparticles tagged with hyaluronic acid to enhance the LDD of the chemotherapeutic agent with overstated drug concentration within lymph nodes (Yang et al. 2019).

Additionally, entry via HEVs may occur following the uptake of therapeutics into immune cells followed by the transfer of the immune cells into lymph nodes via HEVs (Trevaskis et al. 2015). In this regard, the immunosuppressant drug accumulates within lymph nodes via association with lymphocytes in the systemic circulation and subsequent uptake up into lymph nodes, presumably via HEVs (Sensken et al. 2009). The orally administered formulation could be actively transported to LS through M cells located on Peyer’s patches. The mucin layer that covers M cells has a lower thickness compared with other intestinal cells that facilitate contact between nanoparticles and cells (Zhang et al. 2021).

Triggered LDD

The triggered LD approaches are utilized to avoid premature drug release from the nanocarriers before the arrival at the specific site of action (Mahmoud et al. 2022). The triggered nanocarriers can increase drug concentration at a specific site with aid of external or internal stimuli (Raza et al. 2019). Cancer diseases are characterized by marked changes in the cellular microenvironment, therefore, triggered LDDS can be developed to respond to endogenous stimuli associated with the tumor microenvironment (Mahmoud et al. 2022). Likewise, external stimuli including ultrasound, magnetic field, temperature, and light could be used for the same purpose (Mahmoud et al. 2022).

Intrinsic Triggered LDD

Triggered nanocarriers could be fabricated with a material able to disrupt their assembly and release the medicines-loaded cargo once it is exposed to a specific internal change in the microenvironment such as pH, enzymes, redox status, hypoxia, and other endogenous factors associated with the tumor microenvironment (Mahmoud et al. 2022). LS microenvironment could be changed in the same way as the tumor microenvironment once tumor metastasis reaches lymph nodes (Upreti et al. 2013). The endogenous triggering conditions include pH fluctuation, enzyme activation, and changes in the redox status of the cells (Mahmoud et al. 2022). The prodrugs, nanoparticles, and chitosomes are documented to be triggered by pH changes as endogenous stimuli (Mahmoud et al. 2022). In this regard, Chida et al. fabricated pH-triggered nanoparticles to enhance the LDD of chemotherapeutic agents in an acidic microenvironment LS (Chida et al. 2018). In such conditions, nanoparticles exhibited a negative charge at pH 7.4 which converted into a positive charge at lower pH (Raza et al. 2019). Interestingly, the cellular uptake studies of pH-sensitive drug cargoes showed that charge reversal from negative to positive ameliorate their cellular endorsement (Mahmoud et al. 2022). Moreover, the pH sensitivity prodrugs have the capabilities to be activated in cancer cells due to the presence of a hydrazine functional group (Mahmoud et al. 2022). Additionally, redox-responsive delivery systems exhibited higher drug release in the glutathione-enriched medium compared to the glutathione-deprived medium (Mahmoud et al. 2022). Herein, redox-triggered nanoparticles elicited significant cytotoxic effects on cancer cells line compared to normal cells (Raza et al. 2019). Moreover, LDDS could be triggered by enzymes such as N-acetylglucosamine 6-O-sulphotransferase 2 and fucosyltransferase 7 which are solely present in the HEV of the LS (Girard et al. 2012). Taken together, the triggered LDDS could be fabricated to target imaging, anticancer, anti-infective, and immunomodulatory agents in the LS.

Extrinsic Triggered LDD

External stimuli involve the application of an external source of energy like a magnetic field, ultrasound, heat, and light to release the loaded cargo. These approaches could be utilized during the treatment of metastatic cancer within lymph nodes (Li et al. 2019a). In this context, Liang et al. prepared magnetic nanoparticles shelled with a gold shell using a combination of magnetic and phototherapy. The applied magnetic field exaggerates the accumulation of nanocarriers in the targeted lymphatic area followed by the application of radiation to heat the nanocarriers and kill metastatic cancer cells in LS (Liang et al. 2015). Furthermore, Niu et al. prepared nanoparticles containing microbubbles to enhance the delivery of a chemotherapeutic agent to lymph nodes. The prepared nanocarriers release the drug once it is exposed to ultrasound from an external source (Niu et al. 2013). The utilization of ultrasound to trigger the drug release from the cargoes is coupled with the usage of ultrasound contrast agent’s micro/nanobubbles (Mahmoud et al. 2022). Micro/nanobubbles compose of a gas-filled inner core that allows the particles to oscillate at high speed upon exposure exposed to an ultrasound field (El-Sawy et al. 2018). Employing ultrasound affects the integrity of the cell membrane resulting in the formation of tiny pores that enhance the passage of micro/nanobubbles by a process called sonoporation (Mahmoud et al. 2022). Moreover, ultrasound produces cavitation that is characterized by the non-destructive oscillation of micro/nanobubbles with an increase in the blood vessel's permeability to micro/nanobubbles (Mahmoud et al. 2022). Additionally, triggering cargo from thermosensitive nanoparticles using hyperthermia controls the drug release. Herein, inducing hyperthermia triggers drug release from thermosensitive nanoparticles (El-Sawy et al. 2018). Specifically, hyperthermia augments tumor local blood flow, and tumor vascular permeability as well as enhances the nanoparticles trafficking into the tumor tissue, and tumor cell death (Mahmoud et al. 2022).

As well, light-triggered phototherapeutic agents such as hypericin, as well as derivatives of phthalocyanine, hemoglobin, chlorophyll, or other photosensitive substances can selectively kill cancer cells by oxidative damage-mediated mechanisms (Mahmoud et al. 2022). Payload release upon light activation depends on co-loading the intended therapeutic agent with a photothermal agent to form thermosensitive nanoparticles (El-Sawy et al. 2018). The light-triggered release of the drug from these nanoparticles depends on the generation of thermal energy upon exposure to light that activates the photosensitizer (El-Sawy et al. 2018). Upon light activation, the encapsulated photothermal agent raises the temperature of the nanoparticles triggering the release of the payload to achieve the therapeutic effect (Mahmoud et al. 2022). Hypoxia is the potential risk of phototherapy due to oxygen consumption in generating oxidative stress. This generates an anaerobic milieu that may increase the risk of cancer metastasis (Mahmoud et al. 2022).

LDDS

LS-associated diseases such as cancer, organ transplant rejection, infection, inflammation, metabolic disorders, and other diseases pay attention to LDD (Cheng et al. 2022). The LDD is a potential target for drug delivery and enhancing the bioavailability of oral drug supply by avoiding first-pass metabolism. The LS can be targeted via LDDS, the size, and the surface chemistry affect the lymphatic transport of payloads (McCright et al. 2022). The LDDS are lipoproteins bioinspired such as lipid-based nanocarriers, micelles, nanoparticles, and dendrimers (Chaudhary et al. 2014). Among these delivery systems, the lipid-based delivery system is considered to be the best for lymphatic delivery (Chaudhary et al. 2014). The LDD cargoes are administered by the subcutaneous route, intraperitoneal route, pulmonary route, gastric sub-mucosal injection, intrapleural, and intradermal (Chaudhary et al. 2014). The Pegylation of nanoparticles is crucial to maximizing their transport across LEC (McCright et al. 2022). Moreover, PEG density on nanoparticles has the potential to enhance immunotherapeutic outcomes. Both paracellular and micropinocytosis mechanisms underly this transport (McCright et al. 2022). Similar to drug delivery systems, LDD cargoes are challengeable by ample barriers such as universal, organ, cellular, and intracellular barriers (Harisa and Faris 2019). Biomimicry, fabrication of hybrid LDDS, use of PGP inhibitors, and others proposed for overcoming such limitations (Harisa and Faris 2019).

Accordingly, hybrid LDDS can be developed by combining membranes isolated from different cell types or even other synthetic materials by coextrusion (Rodrigues et al. 2022). Therefore, the hybrid cargoes present a structure comprising the different constituents of the original cells (Rodrigues et al. 2022). In this way, hybrid nanomaterials prolonged blood circulation time with increased tumor specificity (Rodrigues et al. 2022). The immune cells could be utilized to engineer lymphotropic LDDS with key ligands for the receptors present in HEV to allow their targeting of the lymph nodes (Girard et al. 2012). Herein, the nanomaterials are camouflaged with macrophages, leukocytes, and dendritic cells or vesicles–derived from immune cells (Rodrigues et al. 2022). Specifically, the vesicles originating from T cells can maintain the T cell receptors that are capable of binding to tumor-derived antigens and constructing a promising tumor-targeted nanomaterial (Rodrigues et al. 2022). Similarly, natural killer cells camouflage nanoparticles to bind malignant cells specifically and stimulate their apoptosis via surface death ligands receptors interaction (Rodrigues et al. 2022). This ligand-receptor interaction is explored by the nanomaterials to potentiate anticancer effectiveness (Rodrigues et al. 2022).

Conventional LDDS

The nanoscale conventional LDDS includes lipid nanoparticles (LNPs), micelles, dendrimers, liposomes, nanoparticles, and other nanomaterials. The delivery systems are documented to deliver the diagnostic and therapeutic agents into the LS (Permana et al. 2021; He et al. 2022). Among these cargoes, LNPs are promising LDDS tools for targeting drugs to the LS due to the inherent lymphatic tropism of these materials in the nanoscale range (He et al. 2022, Noor, 2021, Agrawal et al. 2022). Consequently, LNPs can augment anticancer localization in lymph after metastases of the tumor. This increases the therapeutic effect and lowers the toxicities of anticancer agents (Agrawal et al. 2022). The nonpolar core of LNPs expands the cellular uptake and absorption of lipophilic drugs into the lymph node. Therefore, LNPs are the perfect carrier for treating intracellular infections, such as leishmaniasis, tuberculosis, and parasitic infection (Mitra, 2011). The specific surface modifications with ligands like mannose, or PEG improves macrophage uptake and hence effectively eradicate parasites hiding in macrophages (Agrawal et al. 2022).

During the COVID-19 pandemic, the developed vaccines were loaded with LNPs that stimulate antibody production following lymphatic delivery of mRNA (He et al. 2022, Noor 2021). Pfizer and Moderna companies launched vaccines against the coronavirus that consist of mRNA loaded within LNPs (Weiss et al. 2020). Moreover, the developed LNPs were engineered with polyethylene glycol (PEG) to produce PEGylated LNPs that increase the stability of the prepared formulation during storage (Cross 2021).

Additionally, liposomes have selective targeting of anticancer in lymphatic tissue through subcutaneous and intraperitoneal injections (Li et al. 2019b). The drug entrapped in liposomal vesicles was selectively carried onto lymphatic tissue. The surface modification of liposomes can be to allow for active targeting (Le et al. 2019). Likewise, solid lipid nanoparticles (SLN) shift the drug transport to transmucosal absorption to the lymph stead of the blood, this enhances the drug’s bioavailability (Reddy et al. 2005). Therefore, SLNs are a good strategy for the improvement of the oral bioavailability of drugs with low solubility in GIT or that are vulnerable to first-path and hepatic metabolism (Verma et al. 2021). Furthermore, hyaluronan anticancer-conjugate is the lymphotropic delivery system, consequently, hyaluronan drug-loaded particles are distributed into the lymph nodes following subcutaneous injection compared with free drug (Cai et al. 2008). Similarly, biodegradable nanospheres have been accounted to deliver drugs to the LS. Upon subcutaneous injection of nanospheres, the maximum uptake of the administered cytotoxic drug is distributed into the lymph node (Liu et al. 2006).

As well, anticancer loaded into a small cylinder of biodegradable polylactic acid to target lesions illustrates a higher antitumor effect compared to the drug solution (Liu et al. 2006). Additionally, inorganic nanoparticles such as CaCO₃ nanoparticle-siRNA-loaded vascular endothelial growth factors are documented as LDDS for cancer gene therapy to inhibit cancer lymph node metastasis (He et al. 2008). Moreover, ZnO NPs are reported as LDDS, they enhance the cytotoxicity of anticancer through the improved cellular internalization of nanoparticles by receptor-mediated endocytosis (Zeng et al. 2015).

Moreover, the nanotechnology platform targets LS to fight infectious diseases, and cancer metastasis by targeting the scavenger receptor A1 (SR-A1) (Stevens et al. 2020). These nanoplatforms utilize the poly l-lysine succinylated (PLS) polymer, the lysine side chains are functionalized with Succinyl groups as drug derivatization agents (Stevens et al. 2020). The succinyl groups target SR-A1 which is expressed by myeloid and endothelial cells. Moreover, SR-A1 receptors are highly expressed in cells lining the vasculature and myeloid cells in the lymph nodes (Stevens et al. 2020). Such platforms can improve therapy by increasing the target tissue drug concentrations and reducing systemic drug toxicity. The small molecules, nucleic acids, and peptides can be attached to these platforms with high drug-loading efficiency for diagnostic and therapeutic purposes (Stevens et al. 2020).

Despite the success of conventional drug delivery to deliver therapeutic agents to target cells, however, they still have limitations such as immunogenicity, cytotoxicity, prompt blood clearance, and low bioavailability (He et al. 2022, Noor 2021). Therefore, the use of such drug cargo in clinical applications and still challenging. Consequently, the use of biological delivery systems could evade the limitations associated with the use of conventional drug delivery systems.

Biological LDDS

The biological delivery systems approaches might evade delivery challenges such as biocompatibility, immunological reactions, reducibility, and overcoming the biological barrier (Ren et al. 2016). Cells as well as EVs including exosomes, microparticles, and oncosomes are suggested as a platform for LDD. Among these cargoes, EVs are endogenous cargoes and carry mediators involved in cancer development, and metastasis (Jaiswal et al. 2020). Particularly, oncosomes that carry oncogenic mediators are closely associated with lymphatic cancer metastasis (Zhou et al. 2020). Moreover, EVs can be used as cancer biomarkers or to monitor the efficacy of cancer treatments (Jaiswal et al. 2020). Furthermore, EVs could be used in biotechnology, regenerative medicine, and tissue engineering (Jaiswal et al. 2020). A greater understanding of the role of EVs in tumor metastasis and organotropism is essential for the development of intelligent drug delivery cargoes for specific targeting of anticancer medicines into cell cancer (Jaiswal et al. 2020).

The nanoscale size of exosomes (30 to 200 nm) mediates their drug-targeting capability with high biocompatibility, and the ability to cross biological barriers such as the blood–brain barrier and others barrier (Zhang et al. 2022). In addition to the specific cellular and organ tropism, exosomes could deliver the diagnostic agent as well as therapeutics such as small drugs, macromolecules, proteins, and nucleic acids, in a selective manner (Zhang et al. 2022). Exosomes and other EVs could be isolated and purified from biological fluids or cell culture medium by ample techniques(Zhang et al. 2022). These techniques include ultracentrifugation, sucrose density gradients, tangential flow filtration, size-exclusion chromatography, polymer-based precipitation, and immunoaffinity magnetic beads (Zhang et al. 2022). Additionally, the hybrid exosomes can be generated and loaded with therapeutic or imaging materials such as nucleic acids and other therapeutics (Zhang et al. 2022). Furthermore, exosomes can be functionalized with active targeting moieties to enhance selective uptake by cancer cells. Likewise, exosomes could be used to mantle the conventional synthetic drug cargoes to minimize their immunogenicity (Harisa and Faris 2019). Both direct and indirect methods could be used to mount the drugs into exosomes and other EVs (Sherif et al. 2019).

Among EVs, exosomes are explored for LDD in the term of the blood–lymph barrier. Exosome transfer to the lymph node could provide a mechanism for the rapid exchange of infection-specific information that precedes the arrival of migrating cells, thus priming the node for a more effective immune response (Elliott and He 2021). In this context, exosomal drug delivery could target cancer and other diseases connected with the LS (Elliott and He 2021). In this context, the exosome is distributed to lymph nodes within five minutes and presents for up to two days in the LS (Elliott and He 2021). Also, the exosomes are rapidly transported from interstitial space through lymphatic vessels. In this regard, ample studies utilized exosomes to deliver a therapeutic agent to LS (Olmeda et al. 2021). For example, Park et al. demonstrated that fluorescence-labeled exosomes give strong fluorescence within lymph nodes after subcutaneous administration (Park et al. 2018). Collectively, EVs are LDDS is a promising approach to treating primary tumors of the LS and fighting lymphatic cancer metastases (Elliott and He 2021). Moreover, EVs are devoid of hazardous materials to the environment therefore, they are considered green drug delivery systems(Sherif et al. 2019).

Although EVs are intelligent LDDS, biocompatible, and biodegradable, they still have limitations (Altamimi et al. 2019). The major limitations including the low yield, risk of contamination, infection, and immunogenicity. Moreover, their integrity may be disrupted during collection (Sherif et al. 2019). Therefore, advanced purification techniques are essential criteria to prevent immunological reactions and possible inflammation, however, the biological fluids contain materials rather than exosomes (Zhang et al. 2022). Accordingly, the integration of conventional and biological drug delivery vehicles resulted in the assembly of hybrid delivery systems (Sherif et al. 2019). Figure 4, demonstrates the common conventional, biological and hybrid LDDS.

Fig. 4.

Classification, as well main advantages, and disadvantages of LDDS including conventional, biological, and hybrid LDDS

Hybrid LDDS

The hybrid drug delivery systems consist of conventional and biological constituents in terms of small molecules, macromolecules, supramolecular structures, EVs, viruses, human cells, and bacterial cells (Dehaini et al. 2016; Sato et al. 2016). The hybrid drug delivery systems could be engineered by the grafting of biological, and synthetic ingredients to govern the advantages of both materials (Harisa and Faris 2019). Such cargoes were reported as advanced delivery systems to the liver, spleen, lungs, bone marrow, tumor cells, and other cells (Harisa et al. 2017, 2018). Hybrid LDDS could resolve the biocompatibility problems and prevent the in vivo sequestration of artificial shuttles by the mononuclear phagocytic system (MPS) (Harisa and Faris 2019; Harisa et al. 2017). The hybrid drug cargoes can deliver small therapeutics, DNA, mRNA, therapeutic proteins, antibiotics, anticancer, and other drugs with the ability to overcome biological barriers (Harisa and Faris 2019; Harisa et al. 2017). The engineering of drug delivery not only increases therapeutic efficiency but also reduces systemic toxicity (Harisa et al. 2020). Traditional LDD cargo is transported to the LS based on the inherent distribution and permeability through lymphatic vessels (Permana et al. 2021). However, the hybrid cargo is actively transported to the site of action (Trevaskis et al. 2015).

In comparison with conventional drug delivery systems, the hybrid ones could help with the right diagnosis, and treatment specificity and overcome the limitations (Mitchell et al. 2021). This is attributed to the engineered LDDS overcoming the barriers, intracellular trafficking, cell-specific targeting, and transport to specific organelles, this facilitates the realization and clinical translation (Mitchell et al. 2021). Hybridization approaches are used to enhance tumor uptake as well as tumor specificities such as intratumoral injection, passive targeting, active targeting, and stimuli-responsive nanoparticles (Mahmoud et al. 2022). In sum, hybrid LDDS could be obtained by engineering or grafting drug delivery systems with biological or synthetic agents to produce a hybrid LDDS. Figure 5 and Table 1 summarize the grafting materials used to prepare hybrid LDDS.

Fig. 5.

Schematic representation of biological and non-biological materials used for engineered and production of hybrid LDDS

Table 1.

shows the parameters to be measured with relevant instruments and information obtained

Type of coating material		Coated nanoparticle	Payload	References
Biological
Cells	Erythrocytes	Liposome	5-Fluorouracil	(AlQahtani et al. 2019)
		Hydrogel NPs	Vancomycin	(Zhang et al. 2017)
		Alginate NPs	Arsenic trioxide	(Lian et al. 2019)
	Stem cells	PLGA NPs	Doxorubicin	(Yang et al. 2018)
		Mesoporous silica NPs	Cyanines	(Gao et al. 2016b)
		Nanogel	Doxorubicin	(Gao et al. 2016a)
	Cancer cell	Iron oxide NPs	Doxorubicin	(Zhu et al. 2016)
		PLGA NPs	Antigens	(Fang et al. 2014)
		Mesoporous silica NPs	glucose oxidase	(Xie et al. 2019)
Endogenous carrier	Lipoprotein	Calcium carbonate NPs	Doxorubicin	(Wei et al. 2019)
		PLGA NPs	Atorvastatin	(Zhao et al. 2017)
	Extracellular vesicles	Mesoporous silica NPs	Doxorubicin	(Yong et al. 2019)
		Hyaluronan NPs	–	(Arasu et al. 2017)
Surface antigen	Anti-PSMA mAb	Carbon nanotubes	Paclitaxel	(Comparetti et al. 2020)
	Cetuximab	Magnetic NPs	Doxorubicin	(Dorjsuren et al. 2020)
	HIV-1 surface antigen	LNPs	mRNA	(Saunders et al. 2021)
Bacteria	Escherichia coli	Gold NPs	–	(Gao et al. 2015)
	Mycobacterium smegmatis	Payload materials	Proteins	(Patel et al. 2019)
	Helicobacter pylori	PLGA NPs	–	(Zhang et al. 2019)
Viruses	Simian virus 40	Magnetic NPs	Fluorescent material	(Enomoto et al. 2013)
	Influenza A	Polymeric NPs	mRNA	(Park et al. 2022)
Synthetic
Metal	Silver	Iron oxide NPs	–	(Wang et al. 2011)
	Gold	Iron oxide NPs	–	(Robinson et al. 2010)
Ligands	Hyaluronic acid	Transferosome	Doxorubicin	(Yang et al. 2019)
	Mannose	Polymeric NPs	Ovalbumin	(Salman et al. 2009)
	Lectins	Liposomes	hepatitis B antigen	(Gupta and Vyas 2011)
Polymers	PEG	Polymeric NPs	Fluorescent material	(McCright et al. 2022)
	PCBMA	Gold nanoparticle	–	(Yang et al. 2014)
Ligand and polymer	Folic acid+PEG	SLN	Paclitaxel	(Khatri et al. 2020)
	Mannose+PEG	Polymeric micelles	Saquinavir	(Griffin and O'driscoll 2006)

PSMA prostate-specific membrane antigen, mAb; monoclonal antibody, PCBMA Poly(carboxybetaine methacrylate)

Hybridization of LDDS by Biological Agents

The biological hybridization of conventional LDDS could be achieved by materials obtained from humans, bacteria, and viruses. The substances obtained from human sources include the entire cells, EVs, lipoproteins, plasma proteins, or specific proteins present on the surfaces of the cells (Kiranmai 2017). In this regard, the nanoliposomes loaded with 5-fluorouracil were prepared and grafted with erythrocytes membrane (AlQahtani et al. 2019). Likewise, Gao et al. prepared a doxorubicin-loaded formulation and decorated with stem cells as biological mantle (Gao et al. 2016a). In addition, Zhu et al. used cancer cells as a grafting material to prepare surface bioengineered hybrid iron oxide nanoparticles (Zhu et al. 2016). Likewise, nanoparticles could be engineered with lipoproteins and EVs such as exosomes, oncosomes, and microparticles. From this perspective, Wei et al. use endogenous lipoproteins as a coating material for prepared calcium carbonate nanoparticles (Wei et al. 2019). Additionally, Yong et al. prepared mesoporous silica nanoparticles that incubated cancer cells to produce nanoparticles coated with EVs (Yong et al. 2019). Likewise, Dorjsuren et al. prepared magnetic nanoparticles coated with Cetuximab antibody (Dorjsuren et al. 2020). Moreover, the coating of LDDS could be obtained from microorganisms including bacteria and viruses. In light of this, prepared gold nanoparticles were engineered with Escherichia coli to target the LS (Gao et al. 2015). Similarly, Enomoto et al. developed virus-coated magnetic nanoparticles loaded with the fluorescent agent (Enomoto et al. 2013).

The advantage of these hybrid and biomimetic nanocarriers is the ability to increase circulation time which increases the chance of LDD following infiltration in interstitial space (Mitchell et al. 2021). In addition, cells could be utilized to fabricate the engineered nanoparticles with lymphatic tropism. For example, some of the immune cells including macrophages and T-cells could attain LDD with keys ligand present on their surface with lock receptor present of HEVs. This allows the migration of engineered nanoparticles to lymph nodes (Girard et al. 2012). Furthermore, antigens present on the surface of the microorganisms can enter LS through M cells following oral administration (Dillon and Lo 2019). Based on the literature survey, none of these studies focus on the LDD of fabricated bioengineered nanoparticles. Therefore, there is an urgent demand to study the ability of these biological agents as coated material to increase the LDD of payload cargo.

Hybridization of LDDS by Synthetic Agents

Despite the benefits that could be attained from biological engineering, there are several limitations during the utilization of such agents. For example, the immunogenicity of these agents when they are administered to humans (Bush et al. 2021). Therefore, several studies were performed to use synthetic agents as a coating for nanoparticles. Synthetic agents include polymer and ligand agents. Ligands are usually attached to the surface of nanoparticles to increase drug deposition within the targeted organ and reduce systemic toxicity (Bajracharya et al. 2022). Against this background, Yang et al. prepared nanoparticles decorated with hyaluronic acid to increase drug deposition within LDD. The obtained results showed the ability of the engineered nanoparticles to boost drug concentration within lymph nodes. This is attained by direct access to these particles through HEVs present in the blood capillaries that supply lymph nodes with nutrients (Yang et al. 2019). Alternatively, LS could be accessed through synchronization points between M cells in the intestinal membrane and mesenteric lymph node (Zhang et al. 2021). Within this framework, Salman et al. engineered polymeric nanoparticles with mannose to increase the LDD of immune-stimulant agents to immune cells. An outstanding increase in antibody titer was observed following oral administration compared with subcutaneous injection (Salman et al. 2009).

LDDS could be subjected to surface engineering using synthetic polymers (Dash et al. 2022). Polymers are utilized predominantly to prolong the circulation time of nanoparticles designed for parenteral administration. This is attributed to the shielding effect produced which prevents the adsorption of protein and subsequently avoids the opsonization process (Ejigah et al. 2022). Moreover, this could increase the chance of LDD following the accumulation of nanoparticles within interstitial space (Permana et al. 2021). In light of this, McCright et al. studied the impact of PEG on the LDD of the polymeric nanoparticle. The in-vivo study revealed a 50-fold increase in LDD following the administration of chimeric nanoparticles compared to uncoated nanoparticles (McCright et al. 2022). Most interesting, Pfizer and Moderna companies prepared the second generation of a vaccine against the COVID-19 pandemic. The prepared vaccine was loaded within PEGylated-LNPs increasing the stability and LDD of loaded mRNA (Weiss et al. 2020, Cross 2021).

In the same way, both ligand and polymer-engineered materials could be utilized together to augment drug distribution to LS (Bajracharya et al. 2022; Kumbhar et al. 2022). From this perspective, Khatri et al. developed a PEGylated SLN formulation coated with folic acid. In-vivo results revealed a significant reduction in tumor volume following administration of the prepared formulation compared with a pure chemotherapeutic agent. Fascinatingly, biomarkers screening showed no hepatic and renal toxicity which increases therapeutic outcomes with minimal systemic toxicity (Khatri et al. 2020). Likewise, Griffin and O'driscoll used mannose ligands to prepare chimeric PEGylated polymeric micelles. In-vivo results showed that the prepared formulation was able to increase drug concentration within mesenteric lymph nodes (Griffin and O'driscoll 2006).

Biomedical Applications of LDD

The LDD is essential for treating or targeting specific therapeutic agents such as antiviruses, antibacterial, anticancer, or other medical agents cells into the LS (Singh et al. 2016). Moreover, LDD is proposed to increase the bioavailability of therapeutic molecules susceptible to hepatic first-pass metabolism (Ndayishimiye et al. 2020). Figure 6, illustrates the main biomedical applications of LDD.

Fig. 6.

Schematic illustration of the biomedical application of LDD in the terms of, A) targeting lymphatic disease, B) increasing drug bioavailability, C) boosting the immune system, and D) targeting cancer metastasis

Increase the Drug Bioavailability

The oral route of administration is preferred over others owing to its simplicity, avoiding the need for hospitalization, and training a person (Trevaskis et al. 2015). However, transported therapeutic molecules across enterocytes either passed through portal veins or lymphatic vessels. Therapeutic molecules transported through the portal vein pass through the liver which decreases bioavailability because of hepatic first-pass metabolism (Ndayishimiye et al. 2020). Therefore, the shifting of drug absorption toward the lymphatic path resulted in significant drug bioavailability enhancement (Franco et al. 2020).

In this regard, Ye et al. developed lipid nanoparticles (LNPs) as LDDS to increase raloxifene bioavailability through LS (Ye et al. 2020). Similarly, Rangaraj et al. prepared nanoscaled lipids materials as LDDS to enhance the bioavailability of Ibrutinib through the LS channel. The in-vivo study revealed that the prepared LDDS was able to increase drug bioavailability by 5.3-fold compared to the pure drug (Rangaraj et al. 2020).

Targeting Lymphatic Diseases

Several types of bacteria, viruses, and parasites migrate and colonize within LS that considered a red spot for relapse after completion of therapy. This occurs when the patient is subjected to an appropriate therapeutic protocol and a minimal concentration of the drug is attained within LS (Sunkari and Sunduru 2020). For example, Bacillus anthracis bacteria produce endospores following their phagocytosis by macrophages. Macrophages migrate through LS toward the lymph nodes where endospores are converted into vegetative form (Singh et al. 2016). Similarly, Mycobacterium tuberculosis bacteria are transported from the initial infection site toward lymph nodes. The colonized bacteria within lymph nodes prevent immune cells’ migration toward another part of the body (Chokshi et al. 2019).

Furthermore, maturing of parasitic Leishmania take place in macrophages. Therefore, increased LDD of administered therapeutic agents resulted in increased macrophage exposure to toxic activity produced with the drug (de Souza et al. 2018). Likewise, the life cycle of filariasis usually occurs within lymph nodes where the adult worm is formed. The presence of adult worms within lymphatic vessels resulted in increased vessel dilatation. Therefore, the LDD of therapeutic molecules is essential to ensure the complete eradication of adult worms within lymph nodes (Sarhadi et al. 2022). Additionally, a high level of HIV is detected in mononuclear cells within the lymph node (Woldemeskel et al. 2022). Therefore, LDD of anti-infective agents enhances microbial elimination from the infected LS, ensures complete patient recovery, and avoids relapse following therapeutic protocol (Nasi et al. 2020).

Targeting of Antiviral Agents

Numerous kinds of life-threatening viruses (HIV and AIDS) are hidden within lymph nodes of the LS which rises the propensity of disease relapse. Thus, LDD of antiviral agents besides systemic circulation is required to guarantee complete virus eradication and prevent relapse (Nabi et al. 2019). In this regard, an elevated level of HIV is identified in the blood following infection that subsequently reduces owing to the immune response. Subsequently, virus concentration within the lymph node, particularly mononuclear cells, is intensified compared to systemic circulation (Scholz and Kashuba 2021). Lymphedema is detected in infected patients owing to multiple blockages and destruction of lymphatic vessels. This inhibits the movement of immune cells toward lymph nodes from peripheral tissues followed by a diminished immune response (Woldemeskel et al. 2022). Similarly, following anti-HIV agents’ administration, the virus level in the blood is decreased not the lymph node. This contributed to a rebound rise in viral tiers within systemic circulation following the termination of therapy (Scholz and Kashuba 2021). Consequently, LDD of anti-viral agents encourages viral eradication from the infected lymph nodes and guarantees complete patient recovery. Administration of a loaded multifunction nano-system enhance the delivery of these agents toward lymph node and increase patient quality of life (Nasi et al. 2020).

Targeting the Immunomodulatory Agents

Initially, immunization and vaccination against widespread bacteria and viruses were developed using whole or particles obtained from infectious organisms. Currently, in the second generation of vaccines, the genetic material DNA, or mRNA, has been utilized for this purpose. This strategy represents an innovation in vaccination and gene therapy (Chalbatani et al. 2019; Weiss et al. 2020). Among them, mRNA was utilized during vaccination as a consequence of its ability to stimulate the immune system with high efficiency (Achiron et al. 2021). LNPs have received great attention owing to their inherent tropism toward LS (He et al. 2022, Noor, 2021). Pfizer and Moderna companies launched vaccines against the coronavirus that consist of mRNA loaded within LNPs (Weiss et al. 2020). Moreover, the developed LNPs were engineered with polyethylene glycol (PEG) to produce PEGylated LNPs that increase the stability of the prepared formulation during storage (Cross 2021).

Despite the success of PEGylated LNPs to target LS, these products were administered subcutaneously that require training personnel and special storage conditions. Thus, developing LDDS by oral administration is required to ensure wide distribution and vaccination within a short period (Baker Jr et al. 2022). The Payers’ patches are enriched with M cells that are considered a gateway to LS. Thus, efficient vaccination following oral administration could be attained via mucosal transport through M cells (Zhang et al. 2022). Under these circumstances, Kim et al. deliver ovalbumin to promote dendritic cell activity using nanoparticles. This activates the immune system and prevents the development of melanoma (Kim et al. 2022).

In addition, Yao et al. prepared a surface-modified liposomal formulation loaded with lactoferrin. A pharmacokinetic study revealed a threefold increase in drug bioavailability through LS compared with pure lactoferrin (Yao et al. 2014). Furthermore, Mishra et al. prepared vaccine nanosystems loaded with antigenic material for hepatitis B viruses. The in-vivo study revealed a significant enhancement in antibody levels following oral administration (Mishra et al. 2011).

Targeting of Contrast Agents

Nanomaterials are the potential to enhance the quality of lymphatic imaging due to the specific passive targeting (Qi et al. 2022). Likewise, the engineering of nanomaterials for precise active targeting prolonged the retention of imaging agents in the LS (Qi et al. 2022). Furthermore, multimodal lymphatic imaging based on nanotechnology provides a complementary means to image lymphoid tissues and quantify their function (Qi et al. 2022). Therefore, the development of LDDS has gained increasing attention for cancer diagnosis and tumor therapy (Cheng et al. 2022). The lymphatic imaging modalities detect the staging of cancer lymphatic spread without needless biopsies (Nune et al. 2011; Chaudhary et al. 2014). By mimicking endogenous shuttles such as lipoproteins, the lipid-based delivery system is considered ideal LDDS for diagnostic purposes, they could be administered by the subcutaneous route, intraperitoneal route, pulmonary route, gastric, sub-mucosal injection, intrapleural and intradermal (Chaudhary et al. 2014). In this regard, intravenous administration of contrast agents loaded-nanoparticles is susceptible to phagocytic uptake with mononuclear phagocytic cells and accumulates within the reticuloendothelial system (Upputuri and Pramanik 2020). However, ultra-small nanoparticles tend to accumulate within lymphatic nodes and avoid liver and spleen uptake (Clément and Luciani 2004). Therefore, the administration of nanoparticles allows imaging of the LS for evaluation of cancer grade and detection of cancer metastasis (Polomska and Proulx 2021). This is necessary for the determination of therapeutic protocol during treatment. Therefore, the LDD of administered contrast agents is necessary to achieve maximum therapeutic outcomes during the treatment of metastatic cancer (Skinner et al. 2018). In light of this, various types of ultra-nanoparticles (< 20 nm) loaded with contrast agents were prepared and utilized to select image LS following intravenous administration (Yano et al. 2021; Wang et al. 2017). The lymphatic imaging agents that can localize chemotherapy to the LS improves the treatment and minimizes the exposure of healthy organs to cytotoxic drugs (Nune et al. 2011).

Targeting of Cancer Metastasis

Cancer Metastasis as a Health Problem

Globally, cancer is the second cause of mortality as a result of cancer metastasis. LS is the main channel of cancer metastasis (WHO, 21 September 2021). Particularly, solid tumors including lung, breast, melanoma, and prostate cancers are metastasized across highways of LS (Fares et al. 2020). Cancer metastasis is the separation of cancer cells from the site of the primary tumor to invade the other tissues to form a secondary tumor (Bergers and Fendt 2021). In this regard, cancer cells invade the surrounding tissues or travel into the peritoneal space, blood, or LS to arrest a distant target organ to form a secondary tumor (Bergers and Fendt 2021). The process of cancer cell metastasis includes 4 main steps detachment, intravasation, extravasation, and colonization. In the beginning, cancer cells detached from the primary site and migrated toward stromal tissue (Guan 2015). Once the cell reaches its target, it extravasates from the vessel towards the secondary site. Finally, a secondary tumor is formed at the new site, this process is known as colonization (Ruggiero and Lalli 2021).

The process of cancer metastasis is multifactorial that is produced by genetic, epigenetic, and environmental factors, besides circadian disruptions and aging (Fares et al. 2020). Moreover, the signals that disturb the ECM, growth factors and cytokines, and the microbiota are contributors to carcinogenesis, and cancer metastasis (Mohan et al. 2020). This resulted in the alteration of the biomembranes trafficking mechanism, the malignant transformation, and cancer metastasis (Fares et al. 2020). Particularly, the alteration of the biomembrane’s trafficking is associated with the modulation of enzyme activity, gene expression, cell differentiation, cell cycle progression, cell proliferation, and programmed cell death (Guan 2015). Specifically, the activation of protease enzymes leads to the degradation of the ECM, the inadequacy of the organization of the cell, and tumor cell invasion into the surrounding tissues (Winkler et al. 2020). Additionally, protease enzymes target growth factor receptors, cytokines, chemokines, cell adhesion molecules, apoptotic ligands, and angiogenic factors (Guan 2015). Furthermore, the activation of autophagy is a vigorous process in the metastasis of numerous human cancers (Fares et al. 2020). Herein, autophagy is involved in modulating tumor cell motility and invasion, cancer stem cell viability, and differentiation. Likewise, autophagy plays a role in epithelial-mesenchymal transition (EMT), metastatic cell dormancy, and the escape of cancer cells from apoptosis and the immune system (Fares et al. 2020).

As well, EVs are liberated from the tumor cells that carry mediators that are involved in tumor cell metastasis by alteration of cellular communication, apoptosis, growth, development, and differentiation (Minciacchi et al. 2015; Nicolini et al. 2021). In this regard, the EVs derived from cancer cells known as oncosomes are closely associated with lymphatic cancer metastasis (Pang et al. 2020). During metastatic progression, exosomes can act as messengers that influence important functions in multiple steps of the metastatic cascade including EMT, migration, angiogenesis, and establishment of a pre-metastatic niche (Pang et al. 2020).

LS as a Landscape for Cancer Metastasis

The invasion of cancer cells from the primary site to the blood or lymphatic vessels is attributed to the increased permeability of endothelial membranes (Xu et al. 2013). Therefore, the cancer cells travel through the bloodstream or lymphatic vessels to reach distant organs (Yang et al. 2011; Das et al. 2020). Commonly cancer cells are metastasized through the circulatory system or the LS. The blood cancer metastasis process is not the preferred track for cancer metastasis, however, cancer dies during the blood journey due to harsh environmental conditions associated with oxidative stress and ferroptosis (Vanharanta and Massagué, 2013). Therefore, cancer metastasis within the blood challenged by free radicals and oxidative factors increases the apoptosis of cancerous cells (Guan 2015). This is attributed to the cell membrane of cancer cells being enriched with polyunsaturated fatty acids that are liable to peroxidation by the free radical attack. This increases the chance of programmed cell death, and apoptosis of cancer cells (Ubellacker et al. 2020).

On contrary, the LS system is a good habitat for cancer metastasis, the tumor cells arrive at the lymph nodes through afferent lymphatic vessels (Chaudhri et al. 2016). Lymphatic cancer metastasis is closely associated with tumor relapse, lymph node dissemination is the primary cause of cancer spread (Zhang et al. 2020). The lymphatic fluid showed a favorable milieu for cancer cell survival due to the presence of green media devoid of free radicals and oxidative factors (Grüner and Fendt 2020). Moreover, cancer cells enriched with polyunsaturated fatty acid could survive within lymphatic vessels that are devoid of oxidative stress. Collectively, LS provides an attractive environment for cancer cell metastasis over the bloodstream(Grüner and Fendt 2020). Figure 7 depicts the LS as the main channel of cancer cell metastasis.

Fig. 7.

Metastasis of cancer cells A) to adjacent organ, B) through blood vessels (low frequency), and lymphatic vessels (high frequency)

LS and Cancer Organotropism

Organ tropism means the propensity of the cancer cell to a certain organ, cancer organotropism was first touched by Paget as part of the “seed and soil” hypothesis (Fares et al. 2020). Cancer cell organotropism is the tendency of cancer cells to metastasize and live in a specific organ due to the presence of a suitable milieu (Ventre et al. 2022). The colonization of cancerous cells on the secondary site relays on the plasticity of adapting to the conditions in this area by reshaping their epigenetic landscape (Mortezaee 2021). The host microenvironment plays a vital role in the extravasation and colonization of cancer cells at the specific organ (Fares et al. 2020). Breast cancer metastasis supported this hypothesis for cancer colonization in distant organs (Ventre et al. 2022). In this regard, breast cancer cells commonly metastasize to the bone. The calcium flux is identified as a mechanism of crosstalk between the osteogenic niche and cancer cells promoting bone metastasis (Fares et al. 2020).

Additionally, EVs released by cancer cells such as exosomes, microparticles, and oncosomes are playing a vital role in cancer metastasis (Pang et al. 2020; Jaiswal et al. 2020). EVs are received by organ-specific cell types and produced organotypic metastasis. In this context, breast cancer-derived oncosomes are taken up by endothelial cells in the brain and by fibroblasts in the lungs, resulting in cancer metastasis in the brain and lungs (Pang et al. 2020; Jaiswal et al. 2020). Moreover, pancreatic cancer-derived oncosomes are taken up by Kupffer cells in the liver inducing hepatic cancer (Dong et al. 2021). As well, oncosomes secreted from gastric cancer cells can be delivered to the liver and stimulate liver-specific metastatic cancer (Fares et al. 2020). Table 2 shows tumor tropism of several types of cancers toward other parts of the body.

Table 2.

Cancer metastasis sites from the primary tumor site to secondary sites

Primary site	Secondary site
Lung cancer	Bone, brain, lymph nodes, pleura, liver, kidney, adrenal, thyroid
Colon cancer	Liver, lymph nose, lung, urinary bladder, stomach
Pancreatic cancer	Liver, stomach, colon, and peritoneum
Bladder cancer	Lung, rectum, colon, prostate, ureter, vagina, bone, liver, brain, lymph nose
Breast cancer	Bone, lung, liver, brain, adrenal, lymph node, ovary
Stomach cancer	Liver, lymph node, lung, and bone
Thyroid cancer	Bone, liver, lung
Rectal cancer	Liver, lung, peritonium
Kidney cancer	Lung, liver, and bone
Melanoma	Lymph node, lung, liver, bone, and brain

LDDS and Cancer Targeting

During cancer metastasis, the cancer cells break away from a tumor through the LS to the systemic circulation. However, the fenestration of lymphatic vessels increased up to 500 nm (Zhang and Lu 2014). Therefore, cells are settled in lymph nodes and form a red spot of cancer relapse following the completion of therapy. The subcutaneous injections of nanosystems are absorbed by lymph nodes while orally administered chyle and nanoparticles are absorbed by Peyer’s patches. Furthermore, nanoparticles administered intravenously are rapidly cleared by the reticuloendothelial systems of the lung, liver, and spleen. Lipids-based LDDS aggregate within the lymphatic macrophages. This helps to realize effective drug delivery to the lymphatics to enhance anticancer effects. Accordingly, administrated chemotherapeutic agents should be delivered to the LS at a therapeutic level to ensure the complete elimination of escaped cancer cells (Das et al. 2020). Nano-delivery systems such as liposomes, nano-emulsions, SLN, polymers, activated carbons, silicon, and other LDDS are used to achieve LDD by high drug uptake, release, and accumulation of the drug into metastatic cancer (Maeda et al. 2009). Additionally, the LDD of administered chemotherapeutic agents is necessary for the treatment of different types of cancer such as lymphoma which affects LS (Fang et al. 2018).

Ample studies were conducted to prepare LDDS that could enhance therapeutic outcomes during the treatment of metastatic cancer. For example, Patel and Patel prepared LNPs to enhance the LDD of chemotherapeutic agents following oral administration. In-vivo results showed that the prepared formulation was able to enhance LDD compared to drug suspension (Patel and Patel 2021). Likewise, Yang et al. prepared engineered LDDS loaded within dissolving microneedles. In-vivo results showed the ability of the prepared formulation to increase drug concentration within lymph nodes (Yang et al. 2019). Likewise, Kaminskas et al. prepared nanoparticles to enhance the LDD of the chemotherapeutic agent. The in-vivo study revealed a significant enhancement in drug retention within lymph nodes (about 30%) following subcutaneous injection. On contrary, intravenous injection of chemotherapeutic agents did not transport and delivered to LS (Kaminskas et al. 2015). Similarly, Permana et al. prepared nanoparticles to enhance the LDD of three therapeutic molecules. The in-vivo study revealed a 4–7fold increase in drug concentration within lymph nodes following intradermal injection (Permana et al. 2021). Likewise, Kim and Han prepared nanoparticles loaded with a chemotherapeutic agent. Drug concentration following intramuscular administration in the regional lymph nodes was 100-fold higher compared with systemic circulation (Kim and Han 1995). Additionally, Sherif et al. indicated that the nanoscale lipid cargoes as LDDS could mediate the lymphatic uptake of anticancer to combat lymphatic tumor metastasis (Sherif et al. 2022a). Furthermore, the same authors reported that PEGylated SLN is a promising approach for the lymphatic delivery of anticancer agents (Sherif et al. 2022b).

Conclusion

LD prevents the premature release of payload and mediates selective drug biodistribution. This improves therapeutic impact and reduces the systemic side effect of anticancer, immunomodulatory, and antimicrobial therapeutics. LDDS could be delivered by interstitial injection of nanoparticles to LS through large fenestration present on the lymphatic vessels. Ample approaches including synthesis of prodrugs, stimulation of chylomicron biosynthesis, and fabrication of triggered nanocarriers facilitate LDD. The hybridization of LDDS with biological or synthetic agents produces hybrid LDDS. Hybrid LDDS can be triggered by pH variation, enzyme activation, hypoxia, and redox status as endogenous stimuli. As well, external stimuli such as ultrasound, magnetic field, temperature, and light are used as LDDS triggering agents. Therefore, triggered LDDS are promising diagnostic tools as well as a magic bullet to target lymphatic disease, cancer metastasis, and immunomodulatory agents with increased bioavailability. Thus, triggered LDDS cargoes are a perspective for the delivery of peptides, proteins, chemotherapeutics, immunomodulatory, and antimicrobial agents.

Challenges and Future Horizons

The current LDDS has some limitations such as an insufficient rate of lymphatic, and the biocompatibility of the payloads. Cells and EVs could deliver the therapeutic agents to LS, the fluorescence-labeled exosomes revealed a strong fluorescence within lymph nodes. EVs-derived immune cells enhance the selective uptake of payloads by lymph nodes. The major challenges of biological cargoes are low yield, risk of contamination, infection, immunogenicity, and loss of integrity during collection. The triggered and hybrid LDD systems are a perspective for the delivery of anticancer and immunomodulatory agents. However, the crosstalk between lymph nodes and the whole immune system may induce unwanted immunological reactions. Therefore, extensive effort is useful for the development of biocompatible, and lymphotropic LDDS. The translation of triggered, and hybrid LDDS into industrial, and clinical applications are still challenging.

Author contributions

All authors contributed to the study’s conception and design. Data collection and review were performed by GIH, AYS, and FKA. All authors read and approved the final manuscript.

Funding

The authors extend their appreciation to the Deanship of Scientific Research, King Saud University for funding through Vice Deanship of Scientific Research Chairs, Kayyali Chair for Pharmaceutical Industry, Department of Pharmaceutics, College of Pharmacy, for funding the work through Grant Number AG-2022-6.

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Competing interests

Not applicable.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

All authors agreed to publish the manuscript after acceptance.