Role of borneol as enhancer in drug formulation: A review

Abstract

As a traditional Chinese medicine (TCM), borneol has shown superior ability for anti-inflammatory and analgesic activities when coupled with other active ingredients from ancient times. Furthermore, borneol is believed to improve blood concentration and bioavailability of drugs. Thus, it has been paired with various TCM formulas since ancient time. The physiological barriers in human can cause significant limitations in drug efficiency as the drug is primarily restricted from entering into blood and brain. Borneol has been proven to enhance the permeability of biological barriers such as the blood–brain, transdermal, corneal, and intestinal barriers. Moreover, growing interest has been shown in the drug delivery system design for trans-barrier transport involving borneol. Nano-drug delivery system with increased surface area and improved active sites, has been applied to increase the bioactivity of water insoluble drugs. Nano-drug delivery system has been used to enhance drug efficacy by reducing the time of action as compared to conventional administration approach of TCM formulas. Given its ability to enhance cross-barrier permeation and drug efficacy, borneol has been integrated into TCM formulas of drug delivery system for precise and prolonged targeting at tumor sites. However, the design and preparation of a drug delivery system consisting of borneol still face great challenges. Current research fails to unravel the difference in mechanism of action between nano-drug delivery systems comprised of borneol and conventional drug systems coupled with borneol. Enhanced penetration of borneol in drug delivery system is rarely verified compared to conventional administration with identical drug formulation consisting of borneol regarding dosage and medical indications. This study outlines the current state of research on the properties, formulation and pharmacological effects of borneol, allowing cross-comparison of borneol coupled with single compound and classical TCM formulas for various medical indications. This study aims to provide insights into the design of borneol-based enhanced cross-barrier delivery drug formulation, and the potential development of nano-drug system for TCM formulas with borneol for enhanced bioavailability.

1. Introduction

Borneol has been used in China for more than 1 600 years and initially appeared as a traditional Chinese medicine (TCM) in the Wei, Jin and the Southern and Northern Dynasties (China, 220–589 CE). It was then recorded in the Supplementary Records of Famous Physicians and featured in the Newly Revised Materia Medica in the Tang dynasty (China, 618–907 CE) (Feng, 2024). The heart, spleen, and lung meridians correspond to borneol, described as pungent, bitter, and slightly chilly in the Chinese Pharmacopoeia (2020 edition). It can eliminate heat, awaken the mind, open orifices, and relieve pain. It is used to treat coma, chest paralysis and heartache, red eyes and mouth sores, a sore throat, and ear canal pus (Zhong et al., 2023). Additionally, it is used to treat severe syncope, phlegm syncope, gas depression, and syncope caused by a stroke. Borneol is considered less irritating and is mainly used in eye preparations and pediatric emergency medicine, in well-known formulations such as Suhexiang pills and Suxiao Jiuxin pills, to relieve heat and discomfort. For many years, borneol has been used clinically to treat eye diseases, and 73% of the 76 eye drug formulations in the National Traditional Chinese Medicine Products Collection comprised borneol (Shang et al., 2024).

There are three types of borneol, namely they are L-borneol, D-borneol, and synthetic borneol, with synthetic borneol being by far the most commonly prescribed form. While some studies have not specified the type of borneol used, ‘borneol’ will be used as simplicity for this case. In recent years, in-depth research has shown great interest in borneol, for various purposes, including anti-inflammatory, analgesic, neuronal protection, permeability promotion, chemotherapy sensitization and borneol-modified nano-drug delivery system (Mei et al., 2023; He et al., 2023). Inhibition of the effector pump, opening of tight junction and change of phospholipid bilayer structure are the principles of borneol enhancing the permeability of biological barriers such as brain capillary endothelium, stratum corneum, corneal epithelium and intestinal mucosa (Kulkarni, Sawant, Kolapkar, Huprikar, & Desai, 2021). While it is widely proven that borneol could enhance drug efficacy, aspects such as physical properties and formulations that could be critical in the uptake and transport across barriers are generally neglected in most studies (Zhang, Fu, & Zhang, 2017). It should also be noted that the pairing of borneol in TCM formulas should be restricted with the use of qi-tonifying formulas for the treatment of qi-deficiency, governed by the rule of traditional Chinese medicine practice (Fung & Linn, 2015), whereas the limitation of single components coupled with borneol has not yet been explored. In light of these recent development, a comprehensive review of recent advances and medical indications of borneol is necessary, encompassing its role in TCM formulas and nano-drug delivery systems. This review aims to provide insights into the diverse applications of borneol, shedding light on its potential in advancing therapeutic strategies within the realm of TCM and modern pharmaceutical sciences.

2. Physicochemical and bio-pharmacological characteristics of borneol

The categorization of natural borneol is based on its spin, resulting in two distinct forms namely L-borneol and D-borneol. The former exhibits a specific spin range of +34° to +38°, while the latter falls within the range of −36.5° to −38.5°. D-borneol is obtained through the extraction and processing of branches and leaves of Cinnamomum camphora (L.) Presl (Pan et al., 2014), whereas L-borneol is derived from the extraction and processing of leaves and shoots of Blumea balsamifera (L.) DC., which belongs to the family Asteraceae (Fu, Lu & Ma, 2020). Synthetic borneol is mainly obtained by the reduction of camphor or hydrolysis of α-pinene in turpentine. The three types of borneol share a great extent of morphological similarities and are physically characterized by the formation of massive or flaky crystals, making it a challenge to differentiate among them based on their physical characteristics alone. The 2020 version of the Chinese Pharmacopoeia has established standards on L-borneol, D-borneol, and synthetic borneol (a mixture of L-borneol, D-borneol, D-isoborneol and L-isoborneol) regarding the physiochemical characteristics, as shown in Table 1 and Fig. 1 (Xu et al., 2021). Specifically, the standard strictly defines the content of D-borneol exceeding 96% for all natural borneol, automatically assuming D-borneol as the natural borneol. Additionally, the standard states that natural L-borneol must contain over 80%, while synthetic borneol must contain more than 55% of D-borneol (Ho, Hung, Shih, Yiin, & Chen, 2018).

Table 1.

Physicochemical characteristics of three types of borneol.

Borneol	D-borneol	L-borneol	Synthetic
Sources	Camphoraceae	Blumea balsamifera	N/A
Shape	Crystalline powder or flake crystal	Crystalline powder or flake crystal	Crystalline powder or flake crystal
Scent	Cool camphor	Cool camphor	Cool camphor
Melting point	204 to 209 ℃	201 to 205 ℃	205 to 210 ℃
Rotation	+34° to +38°	−36.5° to −38.5°	Racemate
Isoborneol	None	0.50% (max.)	45% (max.)
Camphor	3.0% (max.)	10.0% (max.)	0.50% (max.)
Purity	≥ 96.0%	≥ 85.0%	≥ 55.0%

Fig. 1.

Chemical structures of borneol stereoisomers: D-borneol, L-borneol, D-isoborneol, L-isoborneol.

Due to the complex nature of the source of borneol, the varying composition, purity and chemical structures could lead to diverse biological effects and potential adverse reactions. The safety concerns of natural borneol are generally negligible compared to synthetic borneol (Chen et al., 2014). The chemical constitution of camphor exhibits a degree of toxicity, particularly its adverse impact on the health of infants and young children (Ding, Ma, & Zhang, 2012). As a result, certain countries have implemented strict regulation on examining the necessity to utilize camphor and requirement on careful usage (Luo et al., 2017). Additionally, it has been reported that high dosage of synthetic borneol significantly reduced the fertility of mice compared to D-borneol, leading to abortion of mid- to late-gestation mice and death of pregnant mice (mortality rates of 60% and 20%, respectively), which may be attributed to the presence of isoborneol in synthetic borneol (Li et al., 2021).

To date, studies on the correlation between physiological and toxicological properties of borneol enantiomers are limited. Therefore, the unique characteristics of these enantiomers in terms of physiological properties and pharmacological effects should be clarified for rational use. Moreover, there is no strict regulation on using these enantiomers of borneol for clinical applications, as they are all defined as borneol. The pharmacokinetics of drugs can be largely influenced by the type of borneol. L-borneol showed a better improvement on drug pharmacokinetics as compared to D-borneol (Saganuwan, 2019), particularly for the treatment of cerebral ischemia/reperfusion (Almeida et al., 2013). Whereas concerns have been raised on the use of L-borneol, and some researches indicated that the use of D-borneol provided a safer treatment choice for central nervous system diseases (Wang, Wang, Tian, Wang, & Zou, 2014).

3. Advances in pharmacological study of borneol

3.1. Analgesic and anti-inflammatory

Borneol is acknowledged for its anti-inflammatory and analgesic characteristics, rendering it a desirable option for managing restricted pain ailments such as joint pain, gingival pain, sore throats, and burns (Zhang, Li, Zhu, Pan, & Guo, 2020). Naturally occurring borneol and its synthetic counterpart exhibit noteworthy anti-inflammatory properties by reducing inflammatory factors, namely NO, TNF-α, and IL-6, in RAW264.7 macrophages. Distinguishable metabolomics of natural borneols could cause superior anti-inflammatory effects compared to synthetic ones (Sun et al., 2019, Zou et al., 2017). As previously reported (Liu et al., 2011), borneol showed great potential to inhibit inflammation in the brain, preventing brain damage. Previous research has demonstrated that the activity of the GABA_A receptor was enhanced by borneol, known as the primary inhibitory neurotransmitter in the brain. The enhancement of GABA_A receptor function has been demonstrated to yield pain-relieving properties (Jiang et al., 2015). It should be stressed that knowledge gap still lies within the compositions of various sources of borneol in the mechanism of act of analgesic activity.

3.2. Antibacterial

Borneol has shown exceptional anti-bacterial effect activity and has been coupled in TCM formulas for external use against bacteria growth, particularly as a treatment approach to chronic eczema (Luo et al., 2024). One study demonstrated significant differences in antibacterial properties of D-borneol, L-borneol, and synthetic borneol against Staphylococcus aureus, β-Streptococcus hemolytic and Escherichia coli (Luo et al., 2014), with D-borneol and L-borneol showing enhanced ability to inhibit bacteria growth than synthetic borneol. Moreover, the antimicrobial actions of the three compounds were observed at low concentrations, and sterilization was reported at high concentrations (Wang et al., 2022).

3.3. Neuroprotective

Edaravone as a recently-approved FDA drug, has long been employed as a therapeutic agent for ischemic stroke in clinical applications (Hu et al., 2022). Serious safety concern has been raised to awareness related to possible edaravone-induced death from cerebral infraction (Xu et al., 2019). Studies indicated that the combined administration of edaravone and borneol (i.e. Edaravone Dexborneol) exhibited synergistic effects in the treatment of ischemic stroke as opposed to the use of edaravone or borneol alone (Zhang et al., 2022).

The amyloid β-protein (Aβ) in the brains of Alzheimer's disease (AD) patients exhibit a lamellar structure that may promote the aggregation of Aβ, leading intractable fibers. The formation of insoluble precipitation in the form of plaques has been identified as contributing to the onset of AD (Thal & Fändrich, 2015). Borneol has been reported to exhibit exceptional potential in the augmentation of superoxide dismutase (SOD) activity (Horváthová et al., 2012), protection of neuron cells from oxidative damage caused by H₂O₂, and efficient prohibition of the accumulation of Aβ in the brain.

Cerebral stroke (stroke) is a sudden cerebrovascular disease associated with significant morbidity, disability, recurrence, and mortality (Akhoundzadeh & Shafia, 2021). Recent study indicated that angiogenesis significantly affected neuroprotection (Ma, Zechariah, Qu, & Hermann, 2012). Furthermore, promoting post-ischemic angiogenesis and providing nourishment to the infarcted region are crucial tactics for enhancing the damage in the ischemic zone (Chang et al., 2017). Both naturally occurring and artificially synthesized borneol exhibited neuroprotective properties (Ma et al., 2021) and stimulating the formation of new blood vessels by elevating levels of Ang-1 and VEGF in rats subjected to a focal cerebral ischemia model. Naturally existing borneol exhibited superior modulating and protective effects on post-ischemic neurovascular units (NVU) compared to synthetic borneol (Xie et al., 2022). This finding indicated that natural borneol may be more suitable for clinical applications in treating central neurological disorders through various types of Chinese medicine products.

3.4. Anti-myocardial damage

Coronary heart disease (CHD), recognized as the number one killer, is on the rise as our population ages and develops more severe cardiovascular and cerebrovascular conditions. There has been significant progress in the research of drugs for the treatment of coronary heart disease. Particularly, quick-acting heart tablets, compound salvia drops, and Angong Niuhuang pills, all consist of borneol, have been commonly prescribed alongside borneol in clinical applications (Fu et al., 2017). Borneol could help to protect the myocardium, possibly by improving myocardial morphology, decreasing the area of myocardial infarction, and improving myocardial function. A possible mechanism might be attributed to their antioxidant actions, the suppression of the inflammatory response, and free radical scavenging (Chen et al., 2019).

Apoptosis, as a form of active cell death, acts as the fundamental mechanism of cellular senescence, growth, and aging in multicellular organisms, as well as maintaining the internal condition. A distinct and complex signaling mechanism governs the precise regulation of the adipogenesis process (Novgorodov et al., 2016). Numerous investigations have reported that the possible cause of apoptosis in cardiac myocytes could be attributed to acute or chronic ischemia as well as ischemia–reperfusion, consequently leading to heart attack (Pistritto, Trisciuoglio, Ceci, Garufi, & D'Orazi, 2016). Both natural and synthetic borneol showed superior ability in cardiomyocyte protection via the mediation of Bcl-2, Bax and Caspase-3 genes, as well as proteins in H9C2 cells (Tong et al., 2022), further mitigating oxidative stress in the cells for apoptosis prevention.

4. Application of borneol I: Penetration enhancer

Natural barriers in the body defend vital organs from external attack while also acting as obstacles preventing therapeutic medications with reduced bioavailability from entering into the body (Kulkarni, Sawant, Kolapkar, Huprikar, & Desai, 2021). As one of the adjuvants that are frequently added in TCM formulas and prescriptions, borneol aims to assist drugs in passing through a variety of physiological barriers, including the blood–brain barrier, mucosal barriers in the nose and stomach, transdermal, transcranial, and blood-optic nerve barriers (Armulik et al., 2010). Vascular endothelial cells (Ferreira, 2019), P-glycoproteins, tight junctions (Hawkins & Davis, 2005), pericytes, and the basal lamina (Fu et al., 2017) are all involved in the intricate process of controlling blood–brain barrier permeability. Due to its capability to alter membrane properties, borneol showed excellent potential for drug delivery across a variety of barriers by altering lipid molecule arrangement and mobility, inhibiting efflux transport proteins, and disrupting the intercellular tight junction proteins (Fan et al., 2015) as shown in Fig. 2.

Fig. 2.

Mechanism on borneol permeation enhancement across various physiological barriers. (A) Distribution of drugs in the brain tissue by lipid bilayer alteration, inhibition of efflux pumps, opening up of tight junctions, or pinocytosis. (B) Enhancement of gastrointestinal mucosal permeability by lipid bilayer alteration, opening of tight junctions and inhibition of efflux pumps. (C) Mechanism of enhanced skin barrier penetration. At lower concentrations of lobelia, the thickness of the bilayer appears to be reduced by lateral expansion. (D) Drug enters the cornea lipid bilayer alteration, opening up of tight junctions.

4.1. Blood-brain barrier (BBB)

The blood–brain barrier (BBB) is upheld by various cellular components referred to as the neurovascular units, consisting of brain microvascular endothelial cells (BMVECs), pericytes, astrocytes, glial cells, neurons, and the extracellular matrix (ECM) (Langen, Ayloo, & Gu, 2019). BMVECs establish complicated tight junctions that seal the cell membrane, creating a robust and impermeable barrier restricting the exchange of substances between the blood and the brain. Maintaining BBB integrity is intricately linked to the structural and functional characteristics of tight junctions in the vascular endothelial cells (Obermeier, Daneman, & Ransohoff, 2013). The expression of Claudin-5 protein, a membrane protein located at tight junctions within the BBB, is essential for establishing tight junctions and plays a crucial role in preserving the structure and functionality of the BBB. A study observed that following a 30 min passive administration of synthetic borneol, the Claudin-5 protein underwent translocation from the endothelial cell membrane of brain capillaries to the cytoplasm, accompanied by alterations in the tight junction structure (Li et al., 2022). This finding shed light on one of the mechanisms through which borneol induced changes in the structure of the BBB itself.

The combined administration of borneol and Chuanxiong Rhizoma demonstrated a synergistic impact on the management of ischemic. Treatment using this combined administration of borneol and Chuanxiong Rhizoma resulted in a significant reduction in cerebral infarction in rats treated with the middle cerebral artery occlusion (MCAO) model. The study revealed that the administration of borneol resulted in enhancement in the microstructure of the BBB. Moreover, borneol facilitated cytokinesis, potentially facilitating the passage of drugs with small molecular weight across the BBB and their subsequent distribution within the brain (Yu et al., 2021). Puerarin and ligustrazine showed great potential in treating cerebral infarction and ischemic. However, their clinical use is hindered mainly due to their poor bioavailability in the brain caused by the low permeability across the BBB. With the combined use of borneol, the distribution of these two compounds showed significant improvement in intracerebral area under the concentration–time curve (AUC_0–12) by more than 1.3-fold (Yin et al., 2017). It is worth noting that these effects are observed with a low dosage of borneol, suggesting that even a low dosage alone can promote the distribution of the drug in the brain. Though the dosage of borneol has been usually neglected, it provides valuable insights into enhancing both brain distribution and oral adsorption that might be observed by increasing the amount of borneol.

4.2. Skin barrier

Transdermal drug delivery systems (TDDS) are recognized for their various benefits, including the ability to bypass initial hepatic metabolism, minimize gastrointestinal irritation, enhance bioavailability, promote patient adherence, prolong drug action, and mitigate adverse effects (Marwah, Garg, Goyal, & Rath, 2016). Nonetheless, the primary obstacle to achieving effective drug delivery through the transdermal pathway lies in the mechanism by which the drug traverses the stratum corneum, which serves as the skin's most impervious barrier (Dumitriu Buzia et al., 2023).

Utilizing an appropriate chemical permeation enhancer is a widely recognized approach to advancing TDDS Permeation enhancers facilitate the transdermal passage of drug molecules by modifying the structure or composition of the stratum corneum. Moreover, permeation promoters regulate the solubility and thermodynamic activity of the drug, thereby promoting its diffusion through the skin (Kapoor, GuhaSarkar, & Banerjee, 2017, Santos, Watkinson, Hadgraft, & Lane, 2012). The permeation-enhancing effects of natural borneol and synthetic borneol on various drug properties have been observed, suggesting that all three types of borneol can serve as transdermal permeation promoters. While there are some differences in the permeation-enhancing effects among the three types in various drug formulations, their overall patterns of permeation enhancement are similar (Yin et al., 2017). Furthermore, the permeation-enhancing effects are particularly notable for hydrophilic drugs or drugs with high molecular weights. Borneol exhibits high lipophilicity, low molecular weight, and volatility, favoring its connection to the lipids in the stratum corneum. Additionally, borneol can induce the formation of temporary pores, which can enhance the penetration coefficient of drugs (Yi, Yan, Tang, Huang, & Kang, 2016).

The permeation-promoting ability of borneol is influenced by temperature and concentration. It has been observed that, within certain boundaries (Luo et al., 2017), the permeation-promoting effect of borneol tends to enhance as the temperature rises. Low concentrations of borneol demonstrated a certain degree of permeation-enhancing capability. However, in the case of strongly hydrophobic drugs like serpentine, higher concentrations of borneol are necessary to facilitate permeation.

4.3. Gastrointestinal barrier

The intestinal mucosal barrier serves as a crucial physiological defense mechanism in the human body, effectively preventing the uptake of toxins and antigens. In contrast, it also restricts the absorption of orally administered medications. The permeability of the epithelial barrier poses a significant obstacle to the absorption of drugs. The primary function of intestinal epithelial cells is to inhibit the passage of toxins and intestinal bacteria into the bloodstream (Martens, Neumann, & Desai, 2018). The intestinal epithelial cells, are densely arranged and interconnected by tight junction proteins. Hence, tight junctions among epithelial cells pose a significant challenge to drug penetration, particularly for large-molecule drugs. Tight junctions among cells serve as a barrier to impede the entry of drugs through extracellular routes. In contrast, lipid bilayer poses challenges for the transcellular transportation of hydrophilic and ionized drugs (Hatayama et al., 2018).

The primary objective of absorption enhancers is to augment the absorption of pharmaceutical substances by promoting cellular permeation within the gastrointestinal tract. Absorption promoters are known to alter the structural integrity of epithelial cells and to enhance the permeation of drugs across the gastrointestinal mucosa. The main mechanisms involve changes in membrane fluidity, modifications in mucus viscosity, and the promotion of tight junction opening between cells. Surfactants (Na, Mao, Wang, & Sun, 2010), fatty acids (Harjoh, Wong, & Caramella, 2020), glycerides (Khatun et al., 2016), bile salts (Osman, & Sultan, 2023), chitosan (Wang et al., 2013), and cholesterol (Aungst, 2012) are frequently used as absorption enhancers. In general, the solubility and adhesion of the drug are augmented, leading to prolonged drug retention at the absorption site and, subsequently, elevated drug bioavailability. The ideal absorption enhancer must strike a delicate balance between two distinct objectives, namely the ability to disrupt the intestinal epithelium for drug uptake and avoiding excessive toxicity.

Borneol is an ideal absorption enhancer with low toxicity, little stimulation to gastrointestinal mucosa and strong permeability. Gao et al. (2019) conducted a feasibility study on enhancing the use of oral curcumin (Cur) with borneol and showed that borneol could promote the apparent permeability coefficient (P_app) of Cur in duodenum, jejunum and ileum through gavage. P_app increased with the increase in borneol concentration given by gavage, while the type of borneol was not specified. The specific causes have not been described, and it is speculated that the function and expression of P-gp, an essential transporter in the small intestine, and multi-drug resistance-related proteins are inhibited. Evidence witnessed a change in the lipid phase of the intestinal mucosa, and the mobility of polar head groups in cell membranes was accelerated. The study conducted comparison of rabbits given ginseng extract only and ginseng extract paired with borneol, the concentrations of NGR1, GRg1 and GRe in the tissues of rabbits administrated ginseng extract with borneol were significantly increased, inhibiting the rapid metabolism of notoginseng saponin R1, ginsenoside Rg1 and Re, possibly by relaxing the tight intercellular connections (Jiang et al., 2014).

The eye is an intricate organ characterized by many barriers that upholds its structural integrity and provide resistance against various infections caused by bacteria, fungi, and viruses. These characteristics also pose challenges in drug delivery to their intended therapeutic targets. The ocular mode of administration is hindered by factors such as tear drainage, limited contact time, and a restricted number of injectable formulations. These limitations contribute to low bioavailability, typically below 5%, and suboptimal therapeutic efficacy (Sasseville et al., 2023). Moreover, intraocular lesions, particularly those located in the posterior segment of the eye, frequently necessitate the administration of intravitreal injections to sustain the desired therapeutic outcome.

The cornea poses a significant obstacle to ocular drug delivery due to its complex structure. The restrictive nature of tight junctions within the corneal epithelium prohibits the passage of hydrophilic drugs, mainly through the transcytosis and paracellular pathways. Consequently, this limitation limits the therapeutic effectiveness of such drugs (Kang-Mieler, Osswald, & Mieler, 2014). Borneol has been used in TCM for more than 1 000 years to treat eye-related diseases. Mainly, licensed products such as Zhenzhu Mingmu eye drops and Ma Yinglong Babao Eye Ointment for eye disease are comprised of borneol in their formulations (Ma, Lu, Wang, Xie, & Guo, 2023). Borneol has been observed to diminish the resistance posed by the corneal epithelial lipid bilayer phospholipids, thereby facilitating the passage of drugs through the cornea (Wu, Huang, Qi, Guo, & Hou, 2006). Additionally, borneol has demonstrated the ability to loosen tight junctions within the corneal epithelium, consequently enabling the paracellular transportation of hydrophilic drugs (Liu et al., 2012).

In order to examine the effect of borneol in the corneal penetration of puerarin eye drops and timolol maleate eye drops, a series of in vitro corneal penetration assays were conducted. Quantitative changes in puerarin and thiamolol maleate corneal penetration were assessed with different dosages of borneol. The results showed that the effect of borneol in promoting corneal penetration was dose-dependent. The permeability effect of borneol in high doses was 9.8 times that of low doses in the puerarin group (Wu, Huang, Qi, Guo, & Hou, 2006). It was suggested that the selective promotion of drug permeability through the cornea using borneol is more pronounced for hydrophilic drugs compared to hydrophobic drugs. Additionally, when 0.1% of borneol was co-administered with 2% polyethylene glycol glycerol caprylate, the absorption of baicalin was approximately 16.35 times higher compared to the group receiving polyethylene glycol glycerol caprylate alone. These findings suggested that the addition of borneol can enhance the corneal permeability of both aqueous and fat-insoluble drugs (Huang, Bai, Yang, Liu, & Cui, 2015). This improvement can be attributed to the ability of borneol to enhance the membrane fluidity of the corneal epithelium, loosen tight intercellular junctions, and facilitate the passage of hydrophilic substances through the epithelium via the paracellular pathway. Consequently, borneol holds the potential for enhanced effect in ophthalmic drug delivery.

5. Application of borneol II: Radiation sensitizer

Radiation therapy is the primary modality employed for the management of unresectable tumors, particularly in cases where surgical intervention is not feasible. Chemotherapeutic agents, such as paclitaxel and cisplatin, are frequently employed as radiotherapy sensitizers in clinical practice. Nevertheless, the concurrent administration of radiotherapy and chemotherapeutic drugs frequently results in an overdosing of toxic adverse effects, posing challenges for patients in terms of tolerability (Morris & Harari, 2014). Recently, there has been a growing interest in non-toxic borneol to augment tumor cells' absorption capabilities in response to chemotherapeutic drugs. This is achieved by impeding the excessive expression of multidrug resistance proteins independently or in conjunction with other drugs (Zhao, Ni, Song, & Hu, 2023).

Doxorubicin (DOX), a chemotherapeutic agent commonly employed as a primary treatment option, has gained extensive utilization in managing various malignancies in human patients. Nevertheless, the clinical application of this treatment is significantly restricted due to the presence of side effects and the development of chemoresistance. The concurrent administration of natural borneol and DOX reduced the level of reactive oxygen species (ROS). Research findings indicated that natural borneol can substantially enhance the anticancer properties of paclitaxel and curcumin. This effect is achieved through the activation of MAPKs and the inhibition of Akt, as demonstrated in multiple studies (Chen et al., 2015, He et al., 2011). The inhibition of P-gp expression has been observed as a potential mechanism for reversing multidrug resistance, with borneol implicated in this process (Prabhakar et al., 2013). Nanoparticles with diameters smaller than 200 nm exhibited enhanced cellular uptake, thereby augmenting the drug's specificity towards cancerous cells.

The introduction of borneol led to a significant reduction in the size of selenium nanoparticles (SeNPs), as documented in the study (Prabhakaret et al., 2013). Treatment with GAL/Borneol@SeNPs demonstrated decreased cytotoxicity in L02 cells while concurrently enhancing the efficacy against drug-resistant hepatocellular carcinoma cells (R-HepG2). Furthermore, the expression levels of ABC transporter proteins (ABCB1, ABCC1, and ABCG2) in R-HepG2 cells were dose-dependently downregulated by GAL/Borneol@SeNPs. This finding aligned with previous studies suggesting that borneol can reverse multidrug resistance by inhibiting the expression of P-gp (Yang, Yi, Luo, & Gong, 2014). Therefore, employing borneol to enhance membrane permeability and inhibit the expression of efflux proteins may represent a promising strategy for addressing multidrug resistance.

6. Preparation of borneol nano-drug delivery system

The utilization of nanotechnology in medicine has become more prevalent in recent years. This is particularly evident in tumor therapy, where the transportation of nanoparticles within the tumor stroma can be hindered by the occurrence of high throughput and retention effects, commonly referred to as the enhanced permeability and retention (EPR) effects, as well as intercellular to intercellular transport. Consequently, the concentration of drugs loaded onto nanocarriers that reach the affected area is minimal, rendering them insufficient in delivering therapeutic effects (Kydd et al., 2017). This obstacle significantly impedes the clinical translation of nanomedicine. Hence, it is of utmost significance to consider the methodologies employed in the administration of nanoparticles and their subsequent transformation and accumulation within the tumor microenvironment.

Nanoparticles within the size range of 20–200 nm have been observed to enhance drug uptake and facilitate passive targeting by exploiting the EPR effects (Wei et al., 2023). Nanocarriers can enhance the duration of in vivo drug circulation by incorporating specific modifiers, diminishing phagocytosis by mononuclear macrophages and reticuloendothelial cells. Several modifications of nanocarriers have been shown to improve the targeting of chemotherapeutic drugs and enhance tumor site accumulation. These modifications include the use of transferrin (Chan et al., 2021), folic acid (Zhang et al., 2020), hyaluronic acid (Song et al., 2018), RGD peptides (Bartneck et al., 2017), and polysaccharide. These modifications enable the nanocarriers to bind to specific receptors highly expressed on the surface of tumor cells. Administration of borneol with drugs has been found to enhance their blood–brain concentration and permeation.

Additionally, incorporating borneol onto the surface of nanoparticles or adding them to drug carriers can improve the accumulation of drugs in tumors and inflammatory tissues (Zhang et al., 2020). This approach holds promising solution for increasing the transmembrane absorption and delivery of nanomedicines to tumor tissues, enabling active targeting, optimal drug release, and desired bio-distribution (Xu et al., 2014). Recent research in this field has been reviewed, highlighting the potential benefits of borneol co-administration with drugs. Modified nanocarriers, such as liposomes, nano-emulsion, poly dendrimers, polymeric micelles, and lipoprotein nanocomposites (Table 2), have been developed to improve the cellular and tissue penetration of nanomedicines and enhance their pharmacodynamic activity.

Table 2.

Overview of micro-nano carrier system of borneol and corresponding preparation technique.

Carriers	Target site	Drug delivery system	Preparation	Characterization	Results	Mechanism	References
Liposome	Brain	Borneol-baicalin liposome (BO-BA-LP)	Reverse evaporative method	Particle size: (156.62 ± 2.96) nm Polydispersity index (PDI): 0.195 Zeta potential: −0.99 mV Encapsulation efficiency (EE): 42.69%	↑ BBB permeability ↑ Expression of some proteins and their genes were significantly upregulated as brain tissue became, damaged after CIRI	BBB opening	Long et al., 2023
	Brain	Ligustrazine-loaded borneol liposomes (LIP@TMP)	Thin-film ultrasonication method	TMP: (282.4 ± 3.6) nm, Drug loading rate (DL): 14.5% ± 0.6%, EE: 42.7% ± 1.0%	↑ Neurological scores, neurogenesis ↓Cerebral infarct volume, inflammation, tissue damage	Apoptosis	Wen et al., 2022
	Brain	Borneol-modified tanshinone IIA liposome (BO-TA-Lip)	High pressure homogenization	Average particle size: (135.33 ± 7.25) nm EE: 85.95% ± 3.20% DL: 4.06% ± 0.31%	↓ Protein expression of NF-κB, ICAM-1, IL-1β, TNF-α and IL-6 in the brain tissue	↓NF-κB, ICAM-1	Ye et al., 2021
	Brain	Borneol angelica polysaccharide liposomes (BAPL)	Solvent evaporation method	Particle size: 179.1 nm Surface zeta potential: −17.2 mV	↓ Infarct volume of TTC, NF-κBp65, TLR-4, IL-8, IL-6, IL-1β ↑ ZO-1, ZO-2, IL-10	BBB opening	Ding et al., 2023
	Brain	Borneol-modified ginkgolides liposomes (GGB-LPs)	Thin-film ultrasonication method	EE: 87.56%. Average particle size: 129 nm	↑ BBB permeability, concentration of GGB-LPs	BBB opening	Lv et al., 2018
	Lung	NBNPs and GFT	High pressure homogenization	Average particle size: approx. 40 nm Hydrodynamic size: 150 nm Conductivity: (125.47 ± 1.05) µs/cm	↑ Cancer-targeting delivery and cytotoxicity of NB in A549 NSCLC cells by specifically identifying and targeting 8 specific proteins	ROS, DNA damage, apoptosis	Yuan, Huang, Chan, He, & Chen, 2020.
Nanoemulsion	Brain	Borneol and Brucea javanica oil nanoemulsion (BBNE)	Phase inversion	Particle size: (47.60 ± 0.57) nm PDI: 0.22 ± 0.01 Zeta potential: (−1.06 ± 0.12) mV DL: (0.424 1 ± 0.005 6) mg/mL	↑ Tumor inhibition rates	BBB opening	Zhang & Zhou, 2014
	Brain	Borneol and lactoferrin co-modified nanoparticles (Lf-BNPs)	Double emulsion solvent evaporation method	Particle size: (175.3 ± 9.6) nm Zeta potential: (−15.7 ± 0.86) mV PDI: 0.129 ± 0.011 EE: 25.43% ± 5.32%	↑Apomorphine-induced contralateral rotations ↓ Dopamine content in the lesioned striatum	Brain-targeted	Tang et al., 2019
Nanoparticle	Brain	Borneol combined with CGKRK peptide modified paclitaxel prodrug self-assembled redox responsive nanoparticles (CGKRK-PSNPs)	Ethanol injection method	Particle size: (105.61 ± 1.53) nm DL: 54.18% ± 1.13%	↑ Sustained release, accumulation of BD-liposome in the brain, the PTX concentration in the brain, the tumor inhibition rates, focal necrosis and nucleus pyknosis ↓ Tumor weight, tumor volume	Enhanced BBB penetration	Lv et al., 2020
	Brain	Ginsenoside-Rh₂ lipid	Ultrasonic assisted solvent evaporation method	Drug loading ratio: 7.2% ± 0.2% EE: 77.3% ± 2.5% Cumulative release (9 h): 52.42%	Dose-dependent killing of glioma cells by nanoemulsion particles	Enhanced BBB penetration	Yu, Wang, Lv, Liu, & Guan, 2023
	Brain	Ganciclovir solid lipid nanoparticles with borneol (GCV-SLN)	Microemulsion-based method	Size: (125.3 ± 4.5) nm PDI: 0.12 ± 0.03 Zeta potential: (−18.3 ± 1.4) mV EE: (67.68 ± 2.80) mV	↑ Distribution of GCV to brain	Enhanced BBB penetration	Ren, Zou, Gao, Wang, & Cheng, 2013
	Brain	BSA modified with borneol (BO) and polyethylene glycol (PEG) (PEG/BO-ITZ-NPs)	Solvent evaporation method	Size: (186.3 ± 1.5) nm PDI: 0.173 ± 0.039 Zeta potential: (−21.03 ± 0.35) mV EE: 78.25% ± 1.84%	↑ About 2-fold higher brain distribution in mice than that of Sporanox	Enhanced BBB penetration	Zhang et al., 2020
	Brain	Tanshinone IIA (TSA) loaded nanoparticles modified by borneol (Bo-TSA-NP)	Double emulsion-solvent evaporation method	Particle size: approx. 160 nm DL: 3.6%	↑ SOD ↓ MDA	Enhanced BBB penetration	Wang et al., 2021
	Brain	Polyethylene Glycol polynorbornene-thiocresol block Copolymers (PEG-PNB-TC) loaded with PTX and curcumin	Thin-film hydration method	EE: 93.78% DL: 2.11%	↑ Blood circulation, drug accumulation, cell uptake of the PEG-PNB-TC micelles, cell killing capability ↓ Drug release, drug clearance	No description	Ding, Sun, Li, Wang, & Mao, 2017
Polymeric micelles	Brain	Conjugated borneol molecules with DSPE-PEG2000-COOH to synthesize a carrier DSPE-PEG2000-BO and loaded with DOX (DOX-BO-PMs)	Coaxial electrospray	Average particle size: (14.95 ± 0.17) nm Zeta potential: (−1.27 ± 0.06) mV EE: 95.69% ± 0.49% DL: 14.62% ± 0.39%	↑ Cellular uptake of DOX-loaded nanomicelles, micelles’ permeability, the transport ratio of DOX BO-PMs, anti-proliferation efficacy, the caspase-3 activity, TUNEL-positive cell ↓ IC50, C6 cell migration, the time to peak in brain, tumor volume, hemorrhaging and necrosis cell	Open the intercellular tight junction; cell apoptosis	Meng et al., 2019
	Brain	A glioma targeted drug delivery system for DOX based on BO- and Folic acid-dual-modified PAMAM (FA-BO-PAMAM/DOX)	Solvent volatilization method	Average size: (22.28 ± 0.42) nm Zeta potential: (7.6 ± 0.89) mV	↑ Inhibition of C6 cells, BBB penetration, C6 cell uptake of DOX, circulating time, AUC0 − inf, T1/2β, MRT, the AUC values in the brain and tumor, the tumor volume inhibitory ratio (%), body weight, rat survival, apoptotic cells in the tumor tissue ↓ Cytotoxicity of PAMAM, volume of distribution (VC), clearance (CL), cardiotoxicity	Enhanced BBB penetration	Li et al., 2015
Dendrimers	Brain	Borneol physical combination with DOX loaded PAMAM dendrimers drug delivery system modified with angiopep-2 (ANG-PEG-PAMAM)	Solvent volatilization method	Size: (21.68 ± 1.04) nm Zeta potential: (9.27 ± 0.40) mV	↑ Transportation ratios for PEG-PAMAM dendrimers and ANG-PEG-PAMAM dendrimers, inhibition effect ↓ Release rates	BBB penetration	Han et al., 2018

Researchers have employed various preparation techniques such as ultrasonic emulsification, double emulsion, solvent evaporation, and chemical methods to fabricate borneol-modified nano-carriers. These nano-carriers exhibit diverse particle sizes, pharmacokinetics, and pharmacodynamics, depending on their modes of administration and therapeutic sites (Guo, Wu, Wang, & Chen, 2019).

In the study (Wang et al., 2021), both physical and chemical methodologies were employed to create a conjugation of borneol and solid lipid nanoparticles (SLN) containing Pueraria lobata flavonoids (PTF). The chemical approach involved the synthesis of borneol-stearic acid (BOSA) conjugates through a reaction between the carboxyl group of stearic acid and the hydroxyl group of borneol, subsequently leading to the formation of PTF-BOSA-SLN through emulsification, evaporation, and coagulation techniques. Additionally, physical approach was adapted in the modification by replacing pure borneol with BOSA during the preparation of solid lipid nanoparticles. Following intranasal administration, the physically modified PTF-BO-SLN (BO denotes borneol) and PTF-BOSA-SLN formulations exhibited a more uniform distribution of PTF in the brain compared to PTF-SLN, with particle sizes ranging from 20 nm to 200 nm. Furthermore, the physically modified PTF-BOSA-SLN facilitated drug delivery via the olfactory route, thus bypassing the BBB. The chemically solid lipid nanoparticle modified with borneol (BO-SLN/CM), physically solid lipid nanoparticle modified with borneol (BO-SLN/PM), and SLN show similar diameter (approximately 87 nm) and morphological characteristics (Song et al., 2018). However, BO-SLN/CM exhibits reduced cytotoxicity, increased cellular uptake, and enhanced permeability across the blood–brain barrier compared to BO-SLN/PM and SLN. Notably, BO-SLN/CM demonstrates remarkable brain targeting ability, while borneol-SLN/PM and SLNs tend to accumulate in the lungs.

7. Conclusion

Borneol has demonstrated significant versatility in the field of micro and nanotechnology design applications. Its utilization extends to a wide range of nanocarriers, including nanoparticles, nanoemulsions, liposomes, dendrimers, and polymer micelles. The integration of borneol in these nano-drug delivery systems has exhibited promising outcomes in the treatment of solid tumors such as lung cancer, breast cancer, brain cancer, and liver cancer. Specifically, the incorporation of borneol has been associated with improvements in drug solubility, enhanced cellular uptake, reduced organ toxicity, and mitigation of multiple drug resistances. These advancements highlight the potential of borneol as a valuable component in the development of innovative and effective therapeutic strategies for combating various types of cancer through micro and nanoscale TCM formulas and drug delivery systems.

While borneol has shown great potential for drug-enhancing effects, the design and development of drug formulation regarding borneol face the following concerns. Most studies should have compared the source and types of borneol. In contrast, only a few studies mentioned synthetic borneol is more irritating to the gastric mucosa and more toxic to the reproduction system than D-borneol. Moreover, differences in optical activity among the three types of borneol including D-borneol, L-borneol and synthetic borneol, could lead to variations in bioactivities and unexpected safety issues. Future research should focus on the knowledge gap between their physicochemical properties and the corresponding biological effects, as well as the gap between conventional administration of TCM formulas and nano DDS consisting of borneol to pursue better drug design and utilization.

CRediT authorship contribution statement

Manqun Tang: Conceptualization, Formal analysis, Writing – original draft, Writing – review & editing. Wenwei Zhong: Conceptualization, Supervision, Writing – original draft, Writing – review & editing. Liwei Guo: Writing – review & editing. Haoran Zeng: Resources, Writing – review & editing. Yuxin Pang: Funding acquisition, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.