Nanotechnology in Therapeutics

A Focus on Nanoparticles as a Drug Delivery System

Suwussa Bamrungsap; Zilong Zhao; Tao Chen; Lin Wang; Chunmei Li; Ting Fu; Weihong Tan

Disclosures

Nanomedicine. 2012;7(8):1253-1271. 

In This Article

Nanocarriers & Their Applications

Various nanoforms have been attempted as drug delivery systems, varying from biological substances, such as albumin, gelatin and phospholipids for liposomes, to chemical substances, such as various polymers and solid metal-containing NPs (Figure 1). Polymer–drug conjugates, which have high size variation, are normally not considered as NPs. However, since their size can still be controlled within 100 nm, they are also included in these nanodelivery systems. These nanodelivery systems can be designed to have drugs absorbed or conjugated onto the particle surface, encapsulated inside the polymer/lipid or dissolved within the particle matrix. As a consequence, drugs can be protected from a critical environment or their unfavorable biopharmaceutical properties can be masked and replaced with the properties of nanomaterials. In addition, nanocarriers can be accumulated preferentially at tumor, inflammatory and infectious sites by virtue of the enhanced permeability and retention (EPR) effect. The EPR effect involves site-specific characteristics, not associated with normal tissues or organs, thus resulting in increased selective targeting. Based on those properties, nanodrug delivery systems offer many advantages,[9–11] including:

Figure 1.

Some nanotechnology-based drug delivery platforms, including a nanocrystal, liposome, polymeric micelle, protein-based nanoparticle, dendrimer, carbon nanotube and polymer–drug conjugate.
NP: Nanoparticle.

  • Improving the stability of hydrophobic drugs, rendering them suitable for administration;

  • Improving biodistribution and pharmacokinetics, resulting in improved efficacy;

  • Reducing adverse effects as a consequence of favored accumulation at target sites;

  • Decreasing toxicity by using biocompatible nanomaterials.

By adopting nanotechnology, fundamental changes in drug production and delivery are expected to affect approximately half of the worldwide drug production in the next decade, totaling approximately US$380 billion in revenue.[12] Next, several main nanocarriers are briefly discussed.

Nanocrystals

One of the most obvious and important nanotechnology tools for product development is the opportunity to convert existing drugs with poor water solubility and dissolution rate into readily water-soluble dispersions by converting them into nanosized drugs.[13,14] In other words, the drug itself may be formulated at a nanoscale such that it can function as its own 'carrier'.[15] Many approaches have been studied, but the most practical strategy involves reducing the drug particle size to nanometer range and stabilizing the drug NP surface with a layer of nonionic surfactants or polymeric macromolecules.[16] By reducing the particle size of the active pharmaceutical ingredient, the drug's surface area is increased considerably, thereby improving its solubility and dissolution and consequently increasing both the maximum plasma concentration and area under the curve. Once the drug is nanosized, it can be formulated into various dosage forms, such as oral, nasal and injectable. These nanocrystal drugs may have advantages over association colloids (micelle solutions) because the level of surfactant per amount of drug can be greatly minimized, using only the amount that is necessary to stabilize the solid–fluid interface.[15]

Furthermore, recent studies have shown that external agents, such as surfactants, for nanocrystal drug delivery can be eliminated. For example, a method was recently developed for the delivery of a hydrophobic photosensitizing anticancer drug in its pure form using nanocrystals.[17] Synthesized by the reprecipitation method, the resulting drug nanocrystals were stable in aqueous dispersion, without the necessity of any additional stabilizer. These nanocrystals are uniform in size distribution with an average diameter of 110 nm. Such nanocrystals were efficiently taken up by tumor cells in vitro, and irradiation of such cells with visible light (665 nm) resulted in significant cell death. An in vivo study of the nanocrystal drug also showed significant efficacy compared with the conventional surfactant-based delivery system. These results illustrate the potential of pure drug nanocrystals for photodynamic therapy. As shown in Table 1 , a number of well-known drugs have already been commercialized using the nanocrystal approach.

Organic Nanoplatforms

Liposomes Liposomes are self-assembled artificial vesicles developed from amphiphilic phospholipids. These vesicles consist of a spherical bilayer structure surrounding an aqueous core domain, and their size can vary from 50 nm to several micrometers. Liposomes have attractive biological properties, including general biocompatibility, biodegradability, isolation of drugs from the surrounding environment and the ability to entrap both hydrophilic and hydrophobic drugs. Through the addition of agents to the lipid membrane, or the alteration of the surface chemistry, liposome properties, such as size, surface charge and functionality, can be easily tuned.

Liposomes are the most clinically established nanosystems for drug delivery. Their efficacy has been demonstrated in reducing systemic effects and toxicity, as well as in attenuating drug clearance.[18,19] Modified liposomes at the nanoscale have been shown to have excellent pharmacokinetic profiles for the delivery of DNA, antisense oligonucleotide, siRNA, proteins and chemotherapeutic agents.[20] Examples of marketed liposomal drugs with higher efficacy and lower toxicity than their nonliposomal analogues are listed in Table 1 . Doxorubicin is an anticancer drug that is widely used for the treatment of various types of tumors. It is a highly toxic compound affecting not only tumor tissue, but also heart and kidney, a fact that limits its therapeutic applications. However, the development of doxorubicin enclosed in liposomes culminated in an approved nanomedical drug delivery system.[21,22] This novel liposomal formulation has resulted in reduced delivery of doxorubicin to the heart and renal system, while elevating the accumulation in tumor tissue[23,24] by the EPR effect. Furthermore, a number of liposomal drugs are currently being investigated, including anticancer agents, such as camptothecin[25] and paclitaxel (PTX),[26] as well as antibiotics, such as vancomycin[27] and amikacin.[28]

Liposomes are also subject to some limitations, including low encapsulation efficiency, fast burst release of drugs, poor storage stability and lack of tunable triggers for drug release.[29] Furthermore, since liposomes cannot usually permeate cells, drugs are released into the extracellular fluid.[30] As such, many efforts have focused on improving their stability and increasing circulation half-life for effective targeting or sustained drug action.[19,31] Surface modification is one method of conferring stability and structural integrity against a harsh bioenvironment after oral or parenteral administration.[32] Surface modification can be achieved by attaching polyethylene glycol (PEG) units, which form a protective layer over the liposome surface (known as stealth liposomes) to slow down liposome recognition, or by attaching other polymers, such as poly(methacrylic acid-co-cholesteryl methacrylate)[33] and poly(actylic acid),[34] to improve the circulation time of liposomes in blood. To overcome the fast burst release of the chemotherapeutic drugs from liposomes, drugs such as doxorubicin may be encapsulated in the liposomal aqueous phase by an ammonium sulphate gradient.[35] This strategy enables stable drug entrapment with negligible drug leakage during circulation, even after prolonged residence in the blood stream.[36] Further efforts to improve control over the rate of release and drug bioavailability have been made by designing liposomes whose release is environmentally triggered. Accordingly, the drug release from liposome-responsive polymers, or hydrogel, is triggered by a change in pH, temperature, radiofrequency or magnetic field.[37] Liposomes have also been conjugated with active-targeting ligands, such as antibodies[38–40] or folate, for target-specific drug delivery.[41]

Polymeric NPs Polymeric NPs are colloidal particles with a size range of 10–1000 nm, and they can be spherical, branched or core–shell structures. They have been fabricated using biodegradable synthetic polymers, such as polylactide–polyglycolide copolymers, polyacrylates and polycaprolactones, or natural polymers, such as albumin, gelatin, alginate, collagen and chitosan.[42] Various methods, such as solvent evaporation, spontaneous emulsification, solvent diffusion, salting out/emulsification-diffusion, use of supercritical CO2 and polymerization, have been used to prepare the NPs.[43] Advances in polymer science and engineering have resulted in the development of smart polymer (stimuli-sensitive polymer), which can change its physicochemical properties in response to environmental signals. Physical (temperature, ultrasound, light, electricity and mechanical stress), chemical (pH and ionic strength) and biological signals (enzymes and biomolecules) have been used as triggering stimuli. Various monomers having sensitivity to specific stimuli can be tailored to a homopolymer in response to a certain signal or copolymers answering multiple stimuli. The versatility of polymer sources and their easy combination make it possible to tune up polymer sensitivity in response to a given stimulus within a narrow range, leading to more accurate and programmable drug delivery.

Polymeric nanocarriers can be categorized based on three drug-incorporation mechanisms. The first includes polymeric carriers that use covalent chemistry for direct drug conjugation (e.g., linear polymers). The second group includes hydrophobic interactions between drugs and nanocarriers (e.g., polymeric micelles from amphiphilic block copolymers). Polymeric nanocarriers in the third group include hydrogels, which offer a water-filled depot for hydrophilic drug encapsulation.

Polymer–Drug Conjugates (Prodrugs) Many polymer–drug conjugates have been developed since the first combination reported in the 1970s.[44,45] Conjugation of macromolecular polymers to drugs can significantly enhance the blood circulation time of the drugs. Especially, protein or peptide drugs, which can be readily digested inside the human body, can maintain their activity by conjugation of the water-soluble polymer PEG (PEGylation). For example, it was reported that PEGylated L-asparaginase increased its plasma half-life by up to 357 h.[46] Without PEG, the half-life of natural L-asparaginase is only 20 h. In addition to PEGylation of proteins, small molecular anticancer drugs can also be PEGylated to improve their pharmacokinetics for cancer therapy. For instance, PEG-camptothecin (PROTHECAN®) has entered clinical trials for cancer therapy.[47]

Increasing the otherwise poor solubility of some drugs is another important function of polymer–drug conjugation. Specifically, conjugating water-soluble polymers to functional groups that already exist in the drug structure can significantly enhance the water solubility of the drug. Recently, a new category of polymer–drug conjugates called brush polymer–drug conjugates were prepared by ring-opening metathesis copolymerization.[48] In this report, as PEG was employed as the brush polymer side chains, the conjugates exhibited significant water solubility. However, polymer–drug conjugates require chemical modification of the existing drugs; as a consequence, their production could cost more, and additional purification steps are needed. Moreover, polymers that are chemically conjugated with drugs are often considered new chemical entities owing to a pharmacokinetic profile distinct from that of the parent drugs. As such, additional US FDA approval is required, even though the parent drug has already been approved. Despite the variety of novel drug targets and sophisticated chemistries available, only four drugs (doxorubicin, camptothecin, PTX and platinate) and four polymers (N-[2-hydroxylpropyl]methacrylamide [HPMA] copolymer, poly-L-glutamic acid [PGA], PEG and dextran) have been used to develop polymer–drug conjugates.[49–54] In addition to the commercially available polymer drugs listed in Table 1 , PGA-PTX (Xyotax™, CT-2103; Cell Therapeutics Inc./Chugai Pharmaceutical Co. Ltd.),[55] PGA-camptothecin (CT-2106; Cell Therapeutics Inc.)[56] and HPMA–doxorubicin (PK1/FCE-28068; Pfizer Inc./Cancer Research Campaign)[57] are now in clinical trials. As an example, PK1 has been evaluated in clinical trials as an anticancer agent, and a Phase I evaluation has been completed in patients with several types of tumors resistant to prior therapy, such as chemotherapy or radiation. However, although the clinical results for HPMA–doxorubicin conjugates look promising, PEG-based conjugation remains the gold-standard in the field of polymeric drug delivery. In addition, polymer–drug conjugates are still limited by their nonbiodegradability and the fate of polymers after in vivo administration.[58]

Polymeric Micelles Polymeric micelles are formed when amphiphilic surfactants or polymeric molecules spontaneously associate in aqueous medium to form core–shell structures. The inner core of a micelle, which is hydrophobic, is surrounded by a shell of hydrophilic polymers, such as PEG.[59] Their hydrophobic core serves as a reservoir for poorly water-soluble and amphiphilic drugs; at the same time, their hydrophilic shell stabilizes the core, prolongs circulation time in blood and increases accumulation in tumor tissues.[41] So far, a large variety of drug molecules have been incorporated into polymeric micelles, either by physical encapsulation[60,61] or covalent attachment.[62] Genexol-PM® (Samyang, Korea), PEG-poly(D,L-lactide)-PTX, employs cremophor-free polymeric micelles loaded with PTX drugs. It was found to have a three-times higher maximum tolerated dose in nude mice and two- to threefold higher levels of biodistribution, compared with those of pristine PTX, in various tissues, including tumors. A Phase I clinical trial has been evaluated in patients, and the results showed that Genexol-PM is superior to conventional PTX for the delivery of higher doses without additional toxicity.[63] Recently, a series of novel dual targeting micellar delivery systems were developed based on the self-assembled hyaluronic acid-octadecyl (HA-C18) copolymer and folic acid-conjugated HA-C18 (FA-HA-C18). PTX was successfully encapsulated by HA-C18 and FA-HA-C18 polymeric micelles, with a high encapsulation efficiency of 97.3%. Since these copolymers are biodegradable, biocompatible and cell-specifically targetable, they become promising nanostructure carriers for hydrophobic anticancer drugs.[64] In addition, stimuli-responsive drug-loaded micelles[65–69] and multifunctional polymeric micelles containing imaging as well as therapeutic agents[70–72] are now under active investigation with the potential to be the mainstream of the polymeric drug development in the near future. Furthermore, using computer simulation, the experimental preparation of drug-loaded polymeric micelles could be more efficiently guided, by providing insight into the mechanism of mesoscopic structures and serving as a complement to experiments.[73]

Hydrogel NPs In recent years, hydrogel NPs have gained considerable attention as one of the most promising nanoparticulate drug delivery systems owing to their unique properties. Hydrogels are cross-linked networks of hydrophilic polymers that can absorb and retain more than 20% of their weight in water, while at the same time, maintaining the distinct 3D structure of the polymer network. Swelling properties, network structure, permeability or mechanical stability of hydrogels can be controlled by external stimuli or physiological parameters.[74–78] Hydrogels have been extensively studied for controlled release of therapeutics, stimuli-responsive release and applications in biological implants.[75,79–81] However, the hydration response to changes in stimuli in most hydrogel systems is too slow for therapeutic applications. To overcome this limitation, further development of hydrogel structures at the micro- and nano-scale is needed.[82] Recent reports showed some progress in micro- and nanogels of poly-N-isopropylacrylamide with ultrafast responses and attractive rheological properties.[83,84] Ding et al. demonstrated that cisplatin-loaded polyacrylic acid hydrogel NPs could be implanted and plastered on tumor tissue.[85] This hydrogel system exhibited superior efficacy in impeding tumor growth and prolonging lifespan in mice. The in vivo biodistribution assay also demonstrated that the hydrogel implant results in high concentration and retention of the drug. A multifunctional hybrid hydrogel was developed by combining the magnetic properties of NPs and the typical characteristics of the hydrogel. These hybrid hydrogels could be used to load a large number of drugs and transport them to the target site by the application of an external magnetic field.[86] To improve the specificity of the hydrogel drug delivery systems, core–shell nanogels were developed, which utilize aptamers as the recognition element and near-infrared light as a triggering stimulus for drug delivery. In this system, gold (Au)–silver nanorods, which possess intense absorption bands in the near-infrared range, were coated with DNA cross-linked polymeric shells, so that drugs can be rapidly and controllably released upon the near-infrared irradiation.[87] As the fate of hydrogel NPs after in vivo administration may be a concern for clinical applications, biodegradable hydrogel NPs with diameters of approximately 200 nm have been synthesized via inverse miniemulsion reversible addition–fragmentation chain-transfer polymerization of 2-(dimethylamino)ethyl methacrylate. A disulfide cross-linker was used to cross-link the NPs, so that the polymer network could be degraded to its constituent primary chains by exposure to a reductive environment. It is indicated that these biodegradable hydrogel NPs are currently being investigated for encapsulation and controlled release of siRNA.[88] Although hydrogel NPs-based drugs are not commercially available, they have high possibility to be further developed for drug delivery systems in the future, owing to their highly biocompatible and effective drug-loading properties.

Protein-based NPs Hydrophobic drugs, such as taxanes, are highly active and widely used in a variety of solid tumor therapies. Both PTX and docetaxel, which are the commercially available taxanes for clinical treatments, are hydrophobic. Because of their solubility problems, they have been formulated as suspensions with nonionic surfactants, such as Cremophor EL® (BASF Corp.) for PTX and Tween-80 (ICI Americas, Inc.) for docetaxel. However, these surfactants are associated with hypersensitivity reaction and toxic side effects to tissues. To decrease toxicity, albumin conjugated with PTX has been formulated, yielding NPs approximately 130 nm in size and approved by the FDA for breast cancer treatment.[89–91] In addition to reduced toxicity, albumin–PTX has been found to bind with the albumin receptor (gp60) on endothelial cells, with further extravascular transport,[92–94] resulting in an increase in drug concentration at tumor sites without hypersensitivity reactions. The albumin–PTX complex is approved in 38 countries for the treatment of metastatic breast cancer. Furthermore, Abraxane® is currently in various stages of investigation for the treatment of other cancers, such as metastatic breast cancer, non-small-cell lung cancer, malignant melanoma, pancreatic and gastric cancer.

Dendrimers Dendrimers are synthetic, branched macromolecules that form a tree-like structure. Unlike most linear polymers, the chemical composition and molecular weight of dendrimers can be precisely controlled; hence, it is relatively easy to predict their biocompatibility and pharmacokinetics.[95] Dendrimers are very uniform with extremely low polydispersities, and they are commonly created with dimensions incrementally grown in approximate nanometer steps from 1 to over 10 nm. Their globular structures and the presence of internal cavities enable drugs to be encapsulated within the macromolecule interior and are used to provide controlled release from the inner core.[96] Although the small size (up to 10 nm) of dendrimers limits extensive drug incorporation, their dendritic nature and branching allows drug loading onto the outside surface of the structure[97] via covalent binding or electrostatic interactions. Dendrimers can be synthesized by either divergent or convergent approaches. In the divergent approach, dendrimers are synthesized from the core and further built to other layers called generations. However, this method provides a low yield because the reactions that occur must be conducted on a single molecule processing a large number of equivalent reaction sites.[98] In addition, a large amount of reagents is required for the latter stages of synthesis, resulting in complication of purification. For the convergent method, synthesis begins at the periphery of the dendrimer molecules and stops at the core. In this approach, each synthesized generation can be subsequently purified.[98]

Drug molecules associated with dendrimers can be utilized for cancer treatment,[99] the enhancement of drug solubility and permeability (dendrimer–drug conjugates)[100] and intracellular delivery.[101] Some drugs can be physically encapsulated inside the dendrimer network or form linkages (either covalently or noncovalently) on the dendrimer surface.[102] Furthermore, functionalization of the dendrimer surface with specific ligands can enhance potential targeting. For example, Myc et al. reported a polyamidoamine dendrimer conjugate containing FA as the targeting agent and methotroxate as the therapeutic agent.[103] Cytotoxicity and specificity were tested with both FA receptor-expressing and nonexpressing cells. Both in vitro and in vivo results showed that the dendrimer conjugate was preferentially cytotoxic to the target cells. The polyamido amine dendrimer conjugated with an anti-prostate specific membrane antigen antibody was also demonstrated.[104] The antibody–dendrimer conjugate specifically bound to anti-prostate specific membrane antigen-positive, but not negative, cell lines. However, dendrimer toxicity and immunogenicity are the main concerns when they are applied for drug delivery. Since the clinical experience with dendrimers has so far been limited, it is hard to tell whether the dendrimers are intrinsically 'safe' or 'toxic'.

Inorganic Platforms

Au NPs Noble metal NPs, such as Au NPs, have emerged as a promising scaffold for drug and gene delivery in that they provide a useful complement to more traditional delivery vehicles. The combination of inertness and low toxicity,[105] easy synthesis, very large surface area, well-established surface functionalization (generally through thiol linkages) and tunable stability provide Au NPs with unique attributes to enable new delivery strategies. Moreover, excess loading of pharmaceuticals on NPs allows 'drug reservoirs' to accumulate for controlled and sustained release, thereby maintaining the drug level within the therapeutic window. An Au NP with 2-nm core diameter could, in principle, be conjugated with 100 molecules to available ligands (n = 108) in the monolayer.[106] Zubarev et al. have recently succeeded in coupling 70 PTX molecules, a chemotherapeutic drug, to an Au NP with a 2-nm core diameter.[107] Efficient release of these therapeutic agents could be triggered by internal (e.g., glutathione[108] or pH[109]) or external (e.g., light[110,111]) stimuli. In addition to serving as the carrier for drug delivery, Au NPs can also be imaged using contrast imaging techniques. Once the Au NPs are targeted to the diseased site, such as a tumor, hyperthermia treatment can be used for tumor destruction. For example, a recent study demonstrated that PEGylated Au NPs were employed for highly efficient drug delivery and in vivo photodynamic therapy of cancer.[112] Compared with conventional photodynamic therapy drug delivery in vivo, PEGylated Au NPs accelerated the silicon phthalocyanine 4 administration by approximately two orders of magnitude without side effects in treated mice. The key issue that needs to be addressed with Au NPs is the engineering of the particle surface for optimized properties, such as bioavailability and nonimmunogenicity.

Superparamagnetic NPs Magnetic NPs have been proposed as drug carriers with a push towards clinical trials.[113] The superparamagnetic properties of iron (II) oxide particles can be used to guide microcapsules in place for delivery by external magnetic fields. Another advantage of using magnetic NPs is the ability to heat the particles after internalization, which is known as the hyperthermia effect. For example, Brazel et al. developed a grafted thermosensitive polymeric system by embedding FePt NPs in poly(N-isopropylacrylamide)-based hydrogels, which can be triggered to release the loaded drug by inducing an increase in temperature based on a magnetic thermal heating event.[114] The grafted hydrogel system is also shown to exhibit a desirable positive thermal response with an increased drug diffusion coefficient for temperatures higher than physiological temperature.[115]

Besides being utilized for targeting and raising temperature, magnetic NPs can also affect the permeability of microcapsules by applying external oscillating magnetic fields and releasing encapsulated materials.[116] For example, ferromagnetic Au-coated cobalt NPs (3 nm in diameter) were incorporated into the polymer walls of microcapsules. Subsequently, application of external alternating magnetic fields of 100–300 Hz and 1200 Oe strength disturbed the capsule wall structures and dramatically increased their permeability to macromolecules. This work supports the hypothesis that magnetic NPs embedded in polyelectrolyte capsules can be used for the controlled release of substances by applying an external magnetic field.

The main benefits of superparamagnetic NPs over classical cancer therapies are minimal invasiveness, accessibility of hidden tumors and minimal side effects. Conventional heating of a tissue by, for example, microwaves or laser light results in the destruction of healthy tissue surrounding the tumor. However, targeted paramagnetic particles provide a powerful strategy for localized heating of cancerous cells.

Ceramic NPs Ceramic NPs are particles fabricated from inorganic compounds with porous characteristics, such as silica, alumina and titania.[117–119] Among these, silica NPs have attracted much research attention as a result of their biocompatibility and ease of synthesis, as well as surface modification.[120–122,301] Furthermore, the well-established silane chemistry facilitates the cross-linking of drugs to silica particles.[123,124] For example, recent breakthroughs in mesoporous silica NPs (MSNs) have brought new possibilities to this burgeoning area of research. MSNs contain hundreds of empty channels (mesopores) arranged in a 2D network of a honeycomb-like porous structure. In contrast to the low biocompatibility of other amorphous silica materials, recent studies have shown that MSNs exhibit superior biocompatibility at concentrations adequate for pharmacological applications.[125,126] Once the vehicle is localized in the cytoplasm, it is desirable to have effective control over the release of drug molecules in order to reach pharmacologically effective levels. The ability to selectively functionalize the external particle and/or the interior nanochannel surface of MSNs is advantageous in achieving this goal.[127,128] Different functional groups can be added by using this methodology, including, for example, functionalization with stimuli-responsive tethers that could be further attached to NPs (Au and iron [II] oxide). These NPs could work as gatekeepers and be removed by either intracellular or external triggers, such as changes in pH, reducing environment, enzymatic activity, light, electromagnetic field or ultrasound.[128] The surface of MSNs can be engineered with cell-specific moieties, such as organic molecules, peptides, aptamers and antibodies, to achieve cell type or tissue specificity. Moreover, optical and magnetic contrast agents can be introduced to develop multipurpose drug delivery systems.

These strategies demonstrated that the application of target-specific MSN vehicles in vitro is promising; however, the application in vivo has not yet been reported. These particles are not biodegradable; consequently, there is a concern that they may accumulate in the human body and cause harmful effects.[117] For further in vivo applications, the biocompatibility, biodistribution, retention, degradation and clearance of MSNs must be systematically investigated.

Carbon-based Nanomaterials Carbon-based nanomaterials have attracted particular interest because they can be surface functionalized for the grafting of nucleic acids, peptides and proteins. Carbon nanotubes (CNTs), fullerene, and nanodiamonds[129] have been extensively studied for drug delivery applications.[130] The size, geometry and surface characteristics of single-wall nanotubes (SWNTs), multiwall nanotubes and C60 fullerenes make them appealing for drug carrier usage. For example, PTX-conjugated SWNTs have shown promise for in vivo cancer treatment. SWNT delivery of PTX affords markedly improved treatment efficacy over clinical Taxol (Bristol-Myers Squibb Co.), as evidenced by its ability to slow down tumor growth at a low PTX dose.[131]

However, the primary drawback of carbon-based nanomaterials appears to be their toxicity. Experiments have shown that CNTs can lead to cell proliferation inhibition and apoptosis. Although they are less toxic than carbon fibers and NPs, the toxicity of CNTs increases significantly when carbonyl, carboxyl and/or hydroxyl functional groups are present on their surface.[132] Because of the reported toxicity of CNTs,[133–137] studies involving their application for drug delivery are still being conducted.[138–140] In order to promote the application of CNTs for drug delivery, researchers have functionalized their surface, rendering them benign.[136] Unfortunately, concerns that functionalized CNTs may revert back to a toxic state if the functional group detaches has limited the pursuit of using these modified CNTs for biomedical applications.

The toxicity of other forms of nanocarbons has also been reported.[132,140,141] One study of human lung tumor cells showed that carbon NPs are even more toxic than multiwall nanotubes and carbon nanofibers.[132] Given the mounting evidence demonstrating the toxicity of carbon NPs, the enthusiasm to develop carbon NPs for drug delivery has decreased significantly in recent years.

Integrated Nanocomposite Particles

A variety of nanoplatforms have been developed for a wide spectrum of applications, and each of these applications has unique advantages and limitations. By combining the specific function of each material, new hybrid nanocomposite materials can be fabricated. For instance, liposomes and polymeric NPs are the two most widely studied drug delivery platforms, and attempts have been made to combine the advantages of both systems. A recent study reported the use of nanocells consisting of nuclear poly(lactic-co-glycolic acid) NPs within an extranuclear PEGylated phospholipid envelope for temporal targeting of tumor cells and neovasculature.[142] Moreover, liposomes are routinely coated with a hydrophilic polymer, such as PEG or poly(ethylene oxide), to improve the circulation time in vivo, which is another example of a liposome–polymer composite.[143] Similarly, liposomal locked-in dendrimers, the combination of liposomes and dendrimers in one formulation, has resulted in higher drug loading and slower drug release from the composite, as compared with pure liposomes.[144] Another LipoMag formulation, which consists of an oleic acid-coated magnetic nanocrystal core and a cationic lipid shell, was magnetically guided to deliver and silence genes in cells and tumors in mice.[145]

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