Nanocapsules Offer Limitless Possibilities
For effective drug delivery in a host of applications, chemists should consider this technology to deliver a wide array of active pharmaceutical ingredients.
Nilish V. Patil
Department of Polymer Engineering & Technology
University of Mumbai Institute of Chemical Technology
A nanocapsule is any nano-sized particle that consists of a shell and a space to hold a desired substance. Nanocapsules formed from lipophilic droplets, as the core, surrounded by a thin wall of polymeric material prepared by anionic polymerization of alkylcyanoacrylate monomer have been proposed as vesicular colloidal polymeric drug carriers.1
Nanocapsules are particulate structures ranging in size between 50nm and 10mu.m, wherein a coat layer separates an inner space from the exterior medium. This property distinguishes nanocapsules from nanospheres; the latter have a uniform cross-section. Structures of similar design are also known in larger dimensions and are then referred to as microcapsules.2 Liposomes and viral capsides are other related structures of nanocapsules.
The benefit of these particles depends on the coat layer used and the preparation method. Common coat layers are made up of crosslinked proteins or interfacial polymers, especially acrylic acid derivatives.3 Coat layers consisting entirely or partially of proteins are of special interest, as they can be designed to be biocompatible and degradable.4 Proteins used in building up are structure-forming, but may also be activity-bearing. Such particles are suitable for the inclusion of foreign substances and in binding other components to the surface. Owing to the natural variety of employable proteins, the surface properties are highly variable and can be adapted to meet various requirements.
These nanocapsules are comprised of branched or hyperbranched polymers and copolymers and have a core-shell structure forming a pocket volume appropriate for complexing and retaining enzymes and other bioactive molecules.5
Synthesis of Nanocapsules
Hydrophobic hollow sphere polymers with diameters ranging from several nanometers to hundreds of micrometers have been developed by polymerization of hydrophobic monomers in the lipid bilayer of vesicles or liposomes.6 The size and shape of the resulting polymer particles are directly determined by the templating vesicles; the polymer scaffold can be modified fairly easily, using conventional chemical reactions.7 The unilamellar vesicles are prepared from the synthetic surfactant by ultrasonification of aqueous lipid dispersions. This yields unilamellar vesicles with an average diameter of 100nm, with a rather high polydispersity. The lipid bilayers of the vesicles were swollen by incubating them in the presence of hydrophobic monomers. A crosslinking polymerization of the monomers was initiated by UV-irradiation at room temperature. The resulting polymer particles were isolated from the vesicles.8
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Another method is the preparation of alkylcyanoacrylate nanocapsules, the special choice of monomer yielding in thinner capsule walls and generally in a more reproducible capsule structure. The sizes of capsules prepared in the described manner depend on the concentrations of the oil and the monomer components. Some capsules from polyalkylcyanoacrylates are synthesized by interfacial polymerization.11 Today, various techniques for the preparation of polyalkylcyanoacrylate nanocapsules have been found which involves the preparation and evaluation of microcapsules formed by the polymerization of methyl methacrylate in the presence of an oil/water macroemulsion. The oil phase was composed of an alkane (e.g., decane or hexadecane), and the oil/water emulsions were stabilized by a variety of emulsifiers. Both oil- and water-soluble initiators were used, and the monomer was introduced by either dissolving in the oil or feeding it through the water phase.12
The penetration or release behavior of various solvents into or from the interior of micrometer-sized monodisperse cross-linked polystyrene/polydivinylbenzene composite particles produces hollow polymer particles by the seeded polymerization utilizing the dynamic swelling method. The crosslinked hollow polymer particles are in the submicrometer size by means of a seeded emulsion polymerization.13
Nanocapsules are also prepared by stabilizing block copolymer vesicles by UV cross-linking. The block copolymer building blocks are also used to generate nanocapsules by cross-linking polymerization of ABA triblock copolymer vesicles, the size of which can be controlled in the range of 50nm up to 500nm.
Due to their crosslinked structure, nanocapsules are shape persistent even after their isolation from the aqueous solution.14
The gold particles are used as templates for the synthesis of hollow polypyrolle capsules. Etching of the gold leaves a structurally intact hollow polymer capsule with a shell thickness governed by polymerization time (5-100nm) and a hollow core diameter dictated by the diameter of the template particle (5-200nm).
Microencapsulation of peptides and proteins involves preparation of microcapsules by using a double emulsion technique. In the induced phase separation method, the aqueous drug solution was intensively mixed with the organic polymer solution while an aqueous surfactant solution was added slowly to the oil-in-water (O/W) emulsion.15 The obtained water-in-oil-in-water (W/O/W) emulsion is stirred under partial vacuum conditions until the organic solvent was removed and the microcapsule was built up.
The development of a new system based on a biodegradable polymer and nanotechnology results in polylactide membrane hemoglobin nanocapsules with a diameter of about 150nm. This is smaller than the lipid vesicles and contains negligible amounts of lipids. We have used biodegradable polymeric nanocapsules to prevent the accumulation of lipid in the reticuloendothelial system.16
Benefits and Applications of Nanocapsules
There are several major advantages of using nanocapsules in drug delivery systems. These advantages include:
• Higher dose loading with smaller dose volumes;
• Longer site-specific dose retention;
• More rapid absorption of active drug substances;
• Increased bioavailability of the drug;
• Higher safety and efficacy and
• Improved patient compliance.
Nanocapsules have a widespread range of applications. For example, confined reaction vessels, drug carriers or protective shells for cells or enzymes have been proposed. Similar and very effective nanometer-sized containers (micelles and vesicular structures) are already used by nature in biological systems. Enclosing biologically-active compounds such as pharmaceutical formulations in nanocapsules delivers the cargo to the site of action, or it could release it over a prolonged period of time. The surrounding membrane is capable of protecting the entrapped active substance from degradation or inactivation. Fluorescent nanocapsules can be used in the determination of stabilities in various media, particularly in biological systems such as stomach contents, intestine contents, serum and lymph.17
Nanocapsules can be used as smart drugs that have specific chemical receptors and only bind to specific cells. It is this receptor that makes the drug “smart,” allowing it to target cancer or disease. Nanocapsules would allow for as much as a 10,000-fold decrease in drug dosages, reducing the harmful side effects of drugs used in chemotherapy. Microcrystals of drugs used to treat serious heart conditions, furosemide and nifedipine, encapsulated with polyions’ and polypeptides’ 40nm shell, can be used to control the release of the drugs. Nanocapsules encapsulate a drug’s active component in a relatively inert “nanocapsule,” which binds and opens in response to a target tissue site. A self-assembling nanoscale polymer carries anticancer drugs across the blood-brain barrier. The encapsulated drug will only target the affected tissue, thus producing fewer side effects.18,19
Protection from Degradation
Nanocapsules are vesicular, reservoir systems in which the drug is confined to a cavity (an oil or aqueous core) surrounded by a unique thin polymeric membrane. Encapsulation is an attractive delivery option for a variety of drugs. It can reduce systemic toxicity, protect vulnerable molecules from degradation in the digestive tract, provide controlled release properties or mask an unpleasant taste. Capsules have a wall thickness of 10-40nm and range from 20nm to 20mm in diameter, with an exact size controlled via the production process.20
The use of nanocapsules as drug carriers is associated with a number of advantages. For example, poly (alkylcyanocrystalate) nanocapsules were shown to protect insulin from degradation by digestive enzymes in vitro and to pass across the interstinal mucosa.21 It was also reported (in rats) that encapsulation of somatostatin analogue within nanocapsules given by oral route improved and prolonged its therapeutic effect22 while encapsulation in chitosan nanoparticles improved a nasal absorption of insulin.23 Moreover, encapsulation provides effective protection of the gastrointestinal mucosa, which was shown by reducing the side-effects of diclofenac24 encapsulated in poly (lactic acid) nanocapsules and also by reducing drug-related irradiation; e.g., after administration in the intramuscular route.25
The Benefits of PEG-based Chemistry
To make drug carriers “invisible” to macrophages and thus to reduce their uptake by phagocytic cells, a special strategy has been applied for preparation of matrix-structured nanospheres. This technique is based on nanoparticle surface modification with polyethylene glycol. PEG provides a “cloud” of hydrophilic chains at the nanoparticle surface to repel plasma proteins.26.27 For example, these particles have been loaded with tamoxifen for antiestrogen therapy in the treatment of hormone-dependent tumors.28 Nanoparticles prepared from PLGA PEG co-polymers have been shown to increase the circulating half-life of cisplatine.29 Similar approaches have been applied to the reservoir-type polymer-based drug carrier nanocapsules with the aim of creating long-circulating systems with a high loading capacity of lipophilic drugs.30 For example, solid tumors were treated with nanocapsules made of PLA PEG loaded with tetra(hydroxyphenyl)chlorin.31
Future prospects for artificial blood, especially of the artificial red blood cells (RBC), have been reported.32-34 And very recently, researchers have developed new artificial RBC that are more like natural RBC. Their novel nano-dimension red blood cell substitute is based on ultrathin polyethylene glycolpolylactic acid (PEG-PLA) membrane nanocapsules (80-150nm diameter) containing hemoglobin (Hb) and enzymes.33 It is worth noting that blood substitutes based on modified hemoglobin, polyhaemoglobins (PolyHb) and perfluorochemicals, are already in advanced phase III clinical trials while conjugated haemoglobins are in phase II clinical trial. And the circulation time of the novel artificial RBC (containing haemoglobin and RBC enzymes with membrane formed from composite copolymer of PEG-PLA) is double that of PolyHb.34
Very recently, it was reported that antisense oligonucleotides could be encapsulated in nanocapsules with a size of 350 + 100nm. A formulation of these capsules might have special importance for oligonucleotide delivery. The first experiments on the treatment of RAS cells expressing the point-mutated Ha-ras gene were promising.35 In another approach, nanocapsules loaded with an aqueous core have been developed for the encapsulation of antisense oligonucleotides. They were shown to effectively protect oligonucleotides from degradation in biological fluids; e.g., in an experimental model of Ewing sarcoma for phosphotrioateantisense oligonucleotides directed against EWS Fli-1 chimeric RNA.36
Hollow Polyelectrolyte (PE) nanocapsules are a promising tool as a drug delivery system because they can be loaded with charged proteins, enzymes or molecules at low pH when wall cavities are in the so-called open state and trap these molecules at higher pH when the pores are in the so-called closed state. Hollow capsules were successfully loaded with FITC-dextran and FITC-BSA.37
Since the only limitation in the choice of cores is the necessity of a charge, a large variety of templates is used, like fixed blood cells,38 ionic crystals,39-41 crystallized fluorescent dyes,42 or proteins.43 Furthermore, the capsule can serve as a protective shell for living cells,44-45 transplants46 or artificial tissue against immune response. In particular, in the field of implants, the encapsulation of tissue material or single cells is promising and a large variety of polymers as well as cell models are still in use.47-48
From the pharmaceutical and medical point of view, some natural polyions are tested to serve as compounds of nanocapsules. For example, a similar dependence on ionic strength of a couple of natural PEs (alginate–oligo-chitosan) on layer thickness and conformational changes were reported.49 Alginate, chitosan, or cellulose derivates seem to be especially promising candidates for the encapsulation studies on transplants and artificial tissue.44,46 But with natural polyions, an unspecific immune response is possible. So, for this field of exploiting applications, several polyion pairs have to be tested for cytotoxicity as well as for the metabolites.
Tailored and Targeted Release
Another important step in the direction of drug delivery systems constructed of polymers with tailored release properties and targeted to specific tissue is the coverage of these capsules especially in the case of synthetic polyions with a bilayer or multilayer of phospholipids. As a result of strong surface charges of the polymer shell, the addition of lipid layers as the uppermost layer is facilitated. Studies reveal a binding of lipid layer to nanocapsules by another layer-by-layer deposition of lipids added as vesicles to the capsules’ suspension.50,51 The interaction between the PE layers and the phospholipid bilayers is so strong that a flip-flop of charged lipid molecules could be observed.52 One advantage of a drug delivery system based on the use of PE nanocapsules instead of liposomes is the higher stability of the capsules, so a passage through the body until the targeted tissue is reached seems possible. Another interesting future application could be the condensation of synthetic PE with DNA or RNA to enhance the transfection rate due to the compensated negative charge of DNA or RNA.53
In the future, nanocapsules will medically functionalize textile fiber as sensors or drug depots. Nanocapsules also have potential future applications in agrochemicals, cosmetics, genetic engineering, wastewater treatments, cleaning products and adhesive component applications. They can be used to encapsulate enzymes, catalysts, oils, adhesives, polymers, inorganic micro- and nanoparticles, latex particles or even biological cells.
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