Addressing Drug Delivery Failures: The Potential of Functionalized Nano/Microcapsules

Abstract

It seems that often excellent drugs are not as effective as they could be due to huge losses of drug molecules before they reach the target destination. The present mini-review attempts to look at ways to address this acute issue, creating Ehrlich’s “magic bullets”, by utilizing functionalized nano/microparticles for drug delivery. These nano/microcapsules have moieties on the external surface that prevent the capsules from accumulating in the wrong places and facilitate their transport to the correct destination, piercing cell membranes and releasing the drug cargo into the cells. Importantly, the drug payload must not be in contact with the environment before reaching the target.

For understandable reasons, pharmaceutical companies prioritize research on the discovery of new medicines. However, it seems that the acute importance of effective delivery of these medicines is not sufficiently recognized. A highly quoted 2016 paper shows that a very small percentage of anticancer molecules carried as nanoparticles reach the target. Data from newer papers , are equally concerning. Wilhelm, Chan, and co-workers offer the following scheme (Scheme ):

1. Wilhelm, Chan et al. Data .

^a Reprinted from Dai, Q.; Wilhelm, S.; Ding, D.; Syed, A. M.; Sindhwani, S.; Zhang, Y.; Chen, Y. Y.; MacMillan, P.; Chan, W. C. W. ACS Nano 2018, 12, 8423–8435.

Other data show that when taking advantage of passive targeting of tumors, the large majority (>95%) of administered nanoparticles accumulate in other organs, in particular the liver, spleen, and lungs. There are no compelling reasons to expect drugs other than anticancer medicines to behave much better.

Reasons for these annoying losses are a follows:

• Nano/microparticles carrying API (active pharmaceutical ingredient) are degraded when traveling in body fluids.

• Nano/microparticles carrying API form agglomerates and thus become immobile.

• Binding caused by “wrong” receptors recognizing specific antibodies (nonspecific binding) results in the particles “parking” in incorrect locations.

• The receptors do recognize the relevant antibodies, but API molecules are not released from nano/microparticles.

One of the most effective ways to successfully deliver API molecules to a desired location is to introduce them into a safe unit, encapsulating them and preventing their contact with the environment for as long as necessary. Taking advantage of nano/microparticles (NMPs) is one approach to address the issue. However, not all nano- and microparticles were created equal. The literature concerning the design, structure, manufacture methods, and applications of nano/microparticles is vast. The following references offer the most relevant reviews. − There are several methods of manufacturing NMPs, including spray drying, coacervation, lyophilization, solvent evaporation, centrifugal extrusion, and interfacial polymerization. Consequently, there are various capsule types. Most nano/microparticles are appropriate for a limited number of applications. NMPs are employed in several industries such as textiles, agriculture, food and beverage, and cosmetics. Particularly important applications seem to be in the pharmaceutical industry. The reasons to encapsulate medicines are as follows:

• It slows down the release of the API. It allows for a prolonged presence of the medicine in the blood or gastrointestinal system at a necessary concentration. Consequently, the drug may be taken less frequently.

• It prevents the premature release of the active compound. For example, enteric coatings can protect the drug in the low stomach pH, which allows a drug to remain unchanged in encapsulated form until it reaches deeper in the gastrointestinal tract, where the pH is higher.

• It ensures a safe delivery of the API to the targeted location. The release of the drug from the capsules must take place only there.

In our opinion, the third possibility offers enormous potential but has not been taken advantage of sufficiently. If we can safely deliver capsules to the desired location, we should be able to release the payload there. Possible release mechanisms include changes in the microenvironment (pH, temperature), the use of focused ultrasound, magnetic or electric field, and enzymatic hydrolysis. The payload-releasing enzymes can be physiological, i.e., located at the targeted location, but they could also be delivered there, perhaps in encapsulated form. Nota bene, it seems effective and elegant to have both API and the capsules’ hydrolyzing enzymes as a payload of nano/microcapsules “parked” in the same location, recognized by the same receptors. Next, a physical trigger, such as a magnetic field, induces the release of enzymes that hydrolyze the polymeric matrix or shell of capsules carrying the enzymes. Thus, we know how to release the API from capsules that were parked at the desired location. Now, we must ensure that the valuable payload is safely delivered to this location. It will require special nano/microparticles. We call them “smart nano/microparticles” (SNMPs).

Let us explore the conceivable and effective options. What are the desired properties that “smart nano/microparticles” (SNMPs) must possess to successfully deliver drug molecules to the correct target? When trying to employ nano/microcapsules to fulfill Paul Ehrlich’s “Zauberkugel” (magic bullet) concept, we should strive to fulfill these traits:

• 1.The molecules of API must not be in any contact with the environment until they reach the final destination. Carriers that have the API coupled or connected to the surface may be very useful, but not for the discussed application. The reservoir (core–shell, medicine molecules are coated with a polymeric shell) type of nano/microcapsules seems to be the most advantageous type. It is worth noting that some authors consider reservoir-type microparticles as microcapsules. Reservoir NMCs can be formed using a few methods, but interfacial polymerization − and complex coacervation are most suitable. Matrix NMCs are another potentially useful type.
• 2.Subcellular delivery is the optimal option in most cases.
• 3.The external surface of nanoparticles must be such that, during transport, it is focused only on reaching the target. As such, it should be as neutral and “nonattractive” as possible and equipped only with the necessary moieties.
• 4.The capsules’ shell must be made of a material that under no circumstances can break or hydrolyze and release the payload prematurely.
• 5.The external surface of capsules must carry protective units preventing early accidents such as the formation of particle agglomerates, accumulation on the surface of “wrong” organs, etc.
• 6.The polymer of the capsules must be such that it will release the payload only when the selected stimulus is applied. Conceivable are stimuli causing relatively slow release (for example, caused by enzymes hydrolyzing the polymeric matrix) or those executing a very rapid release (for example, caused by physical stimuli such as the focused ultrasound resulting in a collapse of the polymeric shell).
• 7.The nano/microparticles’ surface must facilitate crossing unavoidable barriers, , including the entry into specific cells. Therefore, it must be equipped with units suitable for these tasks.
• 8.In most cases, there is a need for a few different moieties on the external surface of capsules. Most technologies for developing nano/microcapsules offer products with a single external moiety. However, methods introducing a variety of units on the external capsules’ surface have been developed as well.

This mini-review explores one of the promising classes of these potential drug delivery tools with a high level of versatility. Nano/microcapsules would have more applications and be more effective if we were able to controllably populate their external surfaces with various chemical moieties. Interfacial polymerization (IP), which was mentioned earlier, is one of many methods of forming nano/microparticles. It produces reservoir capsules, i.e., the payload is not in contact with the environment until the core’s release. Thus, it fulfills one of the critical requirements.

Poncelet and co-workers summarized the benefits of interfacial polymerization:

• It is a simple and reliable process.

• It allows direct control of capsule mean size and membrane thickness.

• It allows high active loading and tunable delivery processes.

• It possesses versatile and stable mechanical and chemical properties of the membrane, as well as membrane permeability.

• It is relatively cheaper and conducive to scale-up.

Standard IP does not produce nano/microparticles with the desired moieties on the particles’ surface. However, a few years ago, we introduced a novel variant of interfacial polymerization manufacturing reservoir nano/microcapsules equipped with several different functionalities on the capsules’ surface. The method is called IPCESCO (Interfacial Polymerization for Capsules’ External Surface Control). As always in IP, the reaction used to form the capsules takes place between monomers dissolved in immiscible phases (oil or water) and takes place at the interface.

A large number of reactions can take advantage of the polymeric shell. The possible polymeric products include polyamides, polyesters, polyethers, polythioethers, polyurethanes, polyureas, polysulfonamides, and polycyclic triazoles (most popular click products). This is an important consideration because it facilitates the use of various enzymes and other triggers for releasing the payload. The size of emulsion droplets during capsules’ manufacture, and thus, the size of capsules in IP depends on the rate of stirring, process temperature, quantity, and type of employed surfactants and can be reasonably well controlled. Monodisperse capsules varying in size from tens of nanometers to hundreds of micrometers have been manufactured using IP. The rate of the polymeric shell formation decreases with time, but increasing temperature and using appropriate phase transfer catalysts allow for achieving the desired shell thickness. The size distribution in IP is often not excellent, but novel methods using microfluidics and emulsion templating , offer significant improvements. For example, Slater and co-workers synthesized microcapsules with excellent size distribution using methylene diisocyanate and tetraethylene pentaamine as polyurea substrates and 2 compressed air pumps to generate flow rates of between 1–100 μL min^–1 (Scheme ). Encapsulation efficiency for IP depends on several factors, such as pH and solubility of API, and is usually between 60 and 80%, but can be above 90%.

2. Thorne, Simkovic, and Slater Data .

^a Optical microscopy image of the oil/water emulsion produced by the microfluidic chip showing size distribution. Reprinted from Thorne, M. F.; Simkovic, F.; Slater, A. G. Scientific Reports 2019, 9,17983.

The general concept of nano/microcapsule formation using IPCESCO is depicted in Scheme . Each monomer carries two or more functionalities, reacting with functional groups of the monomer dissolved in the other phase.

3. Introduction of Functional Groups (Colored Spheres) onto the External Surface of Reservoir Nano/microcapsules.

IPCESCO requires that one or both monomers are additionally equipped with (protected) functional groups, interfering neither with the payload nor with the capsules’ formation. These additional groups end up everywhere in the polymeric shell; however, most importantly, they are present on the external surface of capsules. These “handles” allow for the introduction of various moieties onto the capsules’ surface. Many functional groups, including (protected) hydroxyl, thiol, amino, and carboxyl groups, can act as “handles”. The noncontinuous phase (droplets, functioning as the payload) can encapsulate a broad spectrum of compounds and materials, including magnetic particles and diverse active pharmaceutical ingredients (APIs), ranging from low- to high-molecular-weight species, including proteins, and encompassing both hydrophilic and hydrophobic molecules. Significantly, the number of external surface moieties can be controlled (Scheme ) by employing a selected ratio of monomers containing additional functional groups (not involved in the shell formation) and monomers equipped with no such groups.

4. Control of Capsule Surface “Handles” is Achieved by Reacting a Bifunctional Monomer Bearing Red-Rectangle Functional Groups with a Mixture of Bifunctional Co-monomers .

^a (i) Species bearing blue-rectangle functional groups that introduce nonpolymer-forming moieties (“handles”) and (ii) species lacking nonpolymer-forming moieties.

After the capsule formation, the protected groups are removed, and the functional groups on the surface are reacted with units carrying the desired surface modifiers. For drug delivery applications, they include such diverse compounds as polyethylene glycols, vitamin B12, galactose, N-acetylgalactosamine, lectins, folic acid, and glycoproteins. The more detailed list of successfully utilized surface enhancers can be found in reviews. − Also, approaches to avoid the formation of nanoparticles’ agglomerates in the human body have been discussed.

The most important application of this novel encapsulation technology is in drug delivery. Other applications of novel capsules include an ultrasensitive quantitation and removal of pathogens. While it is not the only methodology to produce capsules carrying various moieties on the external surface, it seems to be the most robust. Alternatively, one can take advantage of grafting onto the particles’ surface. , However, it must be noted that IPCESCO is in an early stage of development.

Here are some of the benefits of capsules equipped with various moieties on the surface:

• Introducing desired properties to the capsules, such as the ability to be recognized by specific receptors, does not affect the structure of the drug. The required chemical functionalities must be present on the capsules’ surface.

• When an API is conjugated to a selected moiety (pro-drug), the molar ratio of the drug to the moiety is usually 1:1. However, when the same API is encapsulated, the number of moieties present on the surface of a single capsule is larger than 1, but still much smaller than the number of molecules of the API inside the capsule. Consequently, a few receptors can attract a small number of capsules but a much larger number of API molecules.

• Almost always, it is much easier to couple the required moieties to the capsules’ surface than directly to the molecules of API. This is because the molecules of API have a specific structure, but one can select the most convenient chemical structure of the monomers forming the shell.

• Since capsules are much larger than molecules of API, it is possible to have many “handles” on the surface of the micro/nanocapsules, and thus, attach several different functional groups, facilitating the capsules’ transport.

• IPCESCO allows for good control of the shell thickness. This enables controlling the rate of the enzymatic release of the API after the capsules reach the target destination.

• There may be circumstances in which it is beneficial to have spacers between the external moieties and the capsules’ surface. These spacers may exhibit specific chemical or physical properties, such as different levels of hydrophobicity, may vary in length or may inhibit the attraction of capsules to locations such as vein walls.

• Arguably, in the near future, the physician knowing the patient’s genotype may want to prescribe a given drug in a nano/microencapsulated form equipped with specific moieties present on the capsules’ external surface. The discussed capsules are ideally suited for such a personalized medicine.

Conclusion and Future Outlook

Often, the delivery of drugs to specific locations is not acceptably effective. The proposed solutions include the necessity of utilizing only carriers that ensure no direct contact of the API with the environment until the release. Matrix and reservoir nano- and microcapsules offer such benefits. Also, the external surface of nano/microcapsules should carry several moieties fulfilling such functions as prevention from forming agglomerates, prevention of nano/microparticles’ attraction to and accumulation in “wrong” places, facilitation of nano/microcapsules crossing various barriers, etc. While one should not expect 100% success, the discussed approach may significantly improve the existing results. It would translate to better patient outcomes (smaller required API doses and lower side effects) as well as improved commercial outcomes. We expect a dramatically increased interest in research and development of novel nano- and microparticles, ensuring that the contact of the API with the patient environment is impossible until capsules reach the final (probably subcellular) destination. Also, novel methods of introducing various moieties onto the capsules’ external surface will be developed.

We gratefully acknowledge financial support from Wilkes University for covering the publication charges associated with this open-access article.

The authors declare no competing financial interest.