Review of Nanobiopolymers for Controlled Drug Delivery

Biodegradable polymeric nanoparticles have attracted attention as potential drug delivery devices due to its bioavailability, biocompatibility, encapsulation, controlled drug release and in drug targeting to organs/tissues, as carriers of DNA in gene therapy, deliver proteins, peptides and genes. Controlled release systems increases therapeutic activity reducing the number of drug administration. This review presents the most outstanding contributions in the field of biodegradable polymeric nanoparticulate systems including poly (lactic-co-glycolic acid), polylactic acid, chitosan, gelatin, poly hydroxy alkaonates, poly caprolactone and poly alkyl cyanoacrylate used as drug delivery system, their synthesis, encapsulation process and drug release mechanisms.     

基于壳聚糖的缓释材料应用研究进展

药物缓释材料种类繁多,壳聚糖因其自身多方面的特性而成为理想的药物缓释载体。文章简要介绍了壳聚糖的缓释机理,且因壳聚糖本身拥有的特殊药理作用,它可用于抗炎、抗癌、抗肺结核及基因类药物载体,模型实验显示均收到了较好的药物缓释效果和相应的治疗效果,因此,本文主要介绍了壳聚糖作为不同药物缓释载体的应用研究进展。     

Microparticles based on hydrophobically modified chitosan as drug carriers

In this work, a hydrophobically modified (HM) chitosan derivative was prepared by covalent linkage of C₁₂ groups to the chitosan backbone. HM‐chitosan microparticles were prepared according to an emulsification‐solvent evaporation method and naltrexone (NTX) was used as a model drug. For comparison, unmodified chitosan and poly lactic‐co‐glycolic acid (PLGA) microparticles were also tested as carriers for NTX. HM‐chitosan formed viscous semi‐dilute solutions, suggesting a high level of chain entanglements and hydrophobic associations. HM‐chitosan microparticles generally showed higher production yield and encapsulation efficiency, as compared with chitosan and PLGA. The burst release shown by chitosan microparticles was significantly reduced when using the HM‐chitosan derivative. An enhanced control of drug release was observed over at least 50 days. PLGA particles demonstrated inferior controlled release properties as compared to HM‐chitosan subsequent to the initial release stage. These results revealed the potential of hydrophobic modification of chitosan as a means to improve the stability and sustained delivery properties of the polymer. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40055.     

pH and magnetic field responsive protein-inorganic nanohybrid conjugated with biotin: A biocompatible carrier system targeting lung cancer cells

Multi-stimuli responsive carrier systems, specifically targeting tumor cells are of high significance to improve the efficacy of cancer chemotherapy. In the present study, we have developed, characterized, and biologically evaluated magnetic casein-calcium ferrite hybrid biopolymeric carrier conjugated with biotin for targeted delivery of cinnamaldehyde to lung carcinoma. The dual stimuli-responsive carrier was successfully synthesized with small size, good stability, and high drug encapsulation efficiency. Natural drug cinnamaldehyde was encapsulated in the hybrid carrier, on which biotin was conjugated to facilitate selective cellular uptake. The prepared drug-carrier system exhibited pH-responsive drug release behavior with a higher release rate under acidic conditions, which can be effectively applied in targeted cancer chemotherapy. The superparamagnetic nature of calcium ferrite enabled magnetically-modulated drug delivery with faster drug release, reaching 85.5% within 4 h, in response to magnetic field stimulus. Kinetic modeling of drug release projected the diffusion-controlled release mechanism. Cell viability assay performed on L929 fibroblast and A549 lung cancer cells verified the biocompatibility and cytotoxicity of the developed formulation, respectively. The nanohybrid carrier significantly increased the anticancer potential of cinnamaldehyde with an 18-fold reduction in the IC₅₀ value, signifying the biotin-functionalized protein-inorganic nanohybrid as an efficient multifunctional platform for targeted drug delivery.     

Synthesis of urea-pyridyl ligand functionalized mesoporous silica hybrid material for hydrophobic and hydrophilic drug delivery application

In this work, we propose the synthesis of urea-pyridyl (UPy) ligand functionalized mesoporous silica hybrid material as novel and effective drug delivery system for loading/release of both hydrophobic and hydrophilic drugs. For the synthesis of UPy ligand functionalized mesoporous silica hybrid material, the combination of sol–gel co-condensation technique and post silica surface modification method were adapted. The prepared UPy ligand functionalized mesoporous silica hybrid (UPy-MSH) material was characterized by X-ray diffraction, Fourier-transform infrared, N₂ adsorption–desorption analysis. The material morphology and mesopore channels were observed by scanning and transmission electron microscopic analyses. The content of modified organic ligand functionalities present in the UPy-MSH material surface was determined by thermogravimetric analysis. The hydrophilic anticancer drug, 5-Fluorouracil and the hydrophobic anti-inflammatory drug, Ibuprofen was used as a model drugs to determine the loading and pH-responsive release efficiency of the synthesized UPy-MSH material under different pH (pH 7.4 and 5.0) conditions, respectively. In addition, the biocompatibility of the UPy-MSH material was evaluated on MDA-MB-231 cells. The experimental results depicted that the synthesized UPy-MSH material is biocompatible and has high drug loading capacity, selective and controlled release of specific drug with respect to the pH condition.     

Biodegradable Nanoparticles-Loaded PLGA Microcapsule for the Enhanced Encapsulation Efficiency and Controlled Release of Hydrophilic Drug

Recently, nano- and micro-particulate systems have been widely utilized to deliver pharmaceutical compounds to achieve enhanced therapeutic effects and reduced side effects. Poly (DL-lactide-co-glycolide) (PLGA), as one of the biodegradable polyesters, has been widely used to fabricate particulate systems because of advantages including controlled and sustained release, biodegradability, and biocompatibility. However, PLGA is known for low encapsulation efficiency (%) and insufficient controlled release of water-soluble drugs. It would result in fluctuation in the plasma levels and unexpected side effects of drugs. Therefore, the purpose of this work was to develop microcapsules loaded with alginate-coated chitosan that can increase the encapsulation efficiency of the hydrophilic drug while exhibiting a controlled and sustained release profile with reduced initial burst release. The encapsulation of nanoparticles in PLGA microcapsules was done by the emulsion solvent evaporation method. The encapsulation of nanoparticles in PLGA microcapsules was confirmed by scanning electron microscopy and confocal microscopy. The release profile of hydrophilic drugs can further be altered by the chitosan coating. The chitosan coating onto alginate exhibited a less initial burst release and sustained release of the hydrophilic drug. In addition, the encapsulation of alginate nanoparticles and alginate nanoparticles coated with chitosan in PLGA microcapsules was shown to enhance the encapsulation efficiency of a hydrophilic drug. Based on the results, this delivery system could be a promising platform for the high encapsulation efficiency and sustained release with reduced initial burst release of the hydrophilic drug.     

Bovine serum albumin gel/polyelectrolyte complex of hyaluronic acid and chitosan based microcarriers for Sorafenib targeted delivery

The development of systems for targeted delivery of Sorafenib in unresectable hepatocellular carcinoma to reduce the systemic toxicity is a challenge. In our article, we successfully prepared core-shell microcapsules based on bovine serum albumin gel with polyelectrolyte complex multilayer shell of polysaccharides with opposite charges, hyaluronic acid, and chitosan, encapsulating Sorafenib, as targeting delivery system for improved hepatocellular carcinoma therapy. A bovine serum albumin gel core was formed by a method based on a sacrificial CaCO₃ template, followed by the multilayer shell build-up of Ca²⁺ cross-linked hyaluronic acid hydrogel, and subsequently alternating multilayers of the polyelectrolyte complex formed between hyaluronic acid and chitosan. The following techniques: Fourier-transform infrared and UV–Vis spectroscopy, X-ray diffraction, differential scanning calorimetry, confocal laser scanning microscopy, atomic force microscopy, and scanning electron microscopy were used for the physicochemical characterization. These tests revealed the spherical shape of core-shell type, the micro-size, as well as the composition of microcapsules after their synthesis and proved the successful encapsulation and release of the drug. The promising results regarding encapsulation efficiency, Sorafenib release profile and cytotoxicity on HepG2 and mesenchymal stem cells, recommend Sorafenib loaded microcapsules as suitable targeted drug carriers for further in vivo studies for hepatocellular carcinoma therapy.     

Nanobiofunctionalized chitosan nanocomposite hydrogel as a highly biocompatible cancer drug carrier

A bio-inspired drug carrier was developed by dual functionalization of chitosan using L-glutamic acid (GA) and phyto-synthesized zinc oxide nanoparticles (ZNPs). A highly porous, three-dimensional network of nanocomposite hydrogel (GA-CHGZ) was obtained upon cross-linking chitosan using biomass-derived dialdehyde cellulose. The hydrogel was optimally loaded with naringenin (NRG) and further characterized using nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and swelling studies. An enhanced NRG loading efficiency of 85.23% was obtained using functionalized hydrogel compared to 52.54% using non-functionalized hydrogel. Delivery studies displayed a maximum release of 69.63% for 1.0 mg/ml of initial NRG concentration at pH 5, which is a highly preferred condition for cancer therapeutics. While ZNPs’ embedment was instrumental in improving the NRG loading and delivery rates, the GA conjugation increased the stability of NRG in the GA-CHGZ, aiding sustained NRG release, which followed a non-Fickian diffusion mechanism with polymer swelling. Antimicrobial potential was explored against Staphylococcus aureus and Trichophyton rubrum strains. The biocompatibility assay using L929 normal cells showed enhanced cell proliferation characteristics for the materials, revealing significant cell viability. The anticancer activity of NRG tested against A431 human skin carcinoma cells increased up to nine-fold with a reduced IC₅₀ value when a functionalized hydrogel was used instead of pure NRG without the nanocomposite carrier. Thus, the bio-functionalized drug–carrier system has a promising application for wound healing and topical skin cancer therapies.     

Polyhydroxyalkanoate‐based drug delivery systems

Microbial polyhydroxyalkanoates (PHAs) have been a subject of significant research interest in the past few decades. The recent development of novel functionalized PHAs has opened up new possibilities to combine the good biocompatibility of PHA‐based drug delivery systems to, for example, improve drug loading and release properties, targeting or imaging functionalities. This mini‐review presents some recent scientific developments in the preparation of functionalized PHAs, PHA–drug and PHA–protein conjugates, multifunctional PHA nanoparticles and micelles as well as biosynthetic PHA particles for drug delivery. These developments in combination with the generally excellent biocompatibility of PHA materials are expected to further expand the interest in PHA materials for drug delivery and other therapeutic applications. © 2016 Society of Chemical Industry     

Preparation and Characterization of Carboxymethyl Chitosan and β-Cyclodextrin Microspheres by Spray Drying

Three kinds of carboxymethyl chitosan/β-cyclodextrin microspheres loaded with theophylline were prepared by spray drying intended for pulmonary delivery. Mucociliotoxicity, permeation rate, and drug release characteristics of the product were investigated. The microspheres obtained by spray drying were found to be spherical with smooth or wrinkled surfaces. The mean particle size was between 3.39 and 6.06 µm. The microspheres demonstrated high product yield (43.7–50.2%), high drug loading (13.7–38.1%), and high encapsulation efficiency (86.9–92.8%). FT-IR indicated that there were interactions of theophylline with carboxymethyl chitosan matrix. Further studies on mucociliotoxicity and permeation confirmed that microspheres had better adaptability and high permeation rate. In vitro drug release from the microspheres was not related to the drug/polymer ratios.     

Poly(L‐histidine)‐chitosan/alginate complex microcapsule as a novel drug delivery agent

Novel poly(L ‐histidine)‐chitosan/alginate complex microcapsules were prepared from biodegradable polymers poly(L ‐histidine) (PLHis) in the presence of chitosan at acetate buffer solution pH 4.6. Microcapsules obtained are spherical and well‐dispersed with a smooth surface and a narrow size distribution. The microcapsules can encapsulate the protein model drug hemoglobin (Hb) efficiently. The results show that the complex microcapsules with low, medium, or high molecular weight of chitosan (0.05%, w/v), the highest encapsulation efficiencies obtained are 91.3%, 85.9%, and 94.2% with loading efficiencies of 47.8%, 44.3%, and 39.7%, respectively. The release profiles indicate that Hb‐loaded microcapsules conform to first‐order release kinetic in whole procedure, and 84.8%, 71.4%, and 87.3% of Hb were released during 72‐h incubation in PBS pH6.8 for microcapsules with low, medium, and high molecular weight chitosan (0.05%, w/v), respectively. The results also indicate that particle size and drug loading efficiency have a significant influence on the release profile and encapsulation efficiency. Our results reveal that the PLHis‐chitosan/alginate complex microcapsules are able to encapsulate and release Hb and are potential carriers for protein drugs. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

分子模拟研究壳聚糖-氮化硼纳米管封装及输运阿霉素

壳聚糖-BNNTs复合载体在药物输运领域存在潜在的应用前景。通过分子动力学方法,以抗癌药物阿霉素DOX为药物模型,研究利用壳聚糖-BNNTs复合载体材料封装及跨膜输运抗癌药物的过程。结果表明,非质子化壳聚糖能吸附且调整DOX以合适的构象进入管中。细胞膜磷脂分子能自发嵌入到BNNT (14,14)管中,将管中壳聚糖挤出并使DOX在管中快速上升。该研究可以为实验提高药物封装效率,并提高癌细胞表面药物浓度提供设计思路。     

载5-氟尿嘧啶壳聚糖/明胶微粒的制备及药物释放性能

壳聚糖及明胶是生物相容性良好的高分子药物载体,制备载5-氟尿嘧啶壳聚糖/明胶微粒,并进行体外释药研究。以石蜡油为外相,壳聚糖/明胶为内相,用乳化交联法制备微粒,以吸附药量为指标,采用正交设计实验优化获得最佳制备条件,用红外光谱、SEM对最佳条件下制备的微粒进行表征。结果表明壳聚糖/明胶微粒的最佳制备条件如下:水油比1:7,壳聚糖/明胶浓度比1:3,乳化剂100.7mmol/L,乳化5min,乳化温度60℃,交联剂戊二醛用量5.5mmol/L,交联时间1h。在此条件下,载药微粒的载药量为34.93%,包封率为38.36%。红外光谱图表明壳聚糖/明胶微粒已负载5-氟尿嘧啶,SEM表明微粒成球状,表面较光滑。模拟胃肠释放表明,微粒具有一定的缓释性能。采用乳化交联法制备载5-氟尿嘧啶壳聚糖/明胶微粒方法简单,重现性好,且其体外释放实验显示出明显的缓释作用。     

Polymeric micelle composed of PLA and chitosan as a drug carrier

Water soluble chitosan (CS) oligomer was hydrophobically modified with PLA unit. The chemical structure and physical properties of CS derivatives were confirmed by FTIR, ¹HNMR, TGA and X-RD. Formation and characteristics of polymeric micelles of graft copolymers were studied by fluorescence spectroscopy and dynamic light scattering (DLS) method. To estimate the feasibility as novel drug carriers, the copolymer micelles were prepared by the phase separation-dialysis method. Rifampin was incorporated into polymeric micelles as a lipophilic model drug to investigate the drug release behavior. As PLA weight ratio increased, the micelle size and drug-loading content increased, and the drug release rate decreased.     

Preparation of new dendrimer‐like star‐shaped amphiphilic poly(ethylene glycol)–poly(ϵ‐caprolactone) copolymers for biocompatible and high‐efficiency curcumin delivery

Novel amphiphilic star‐shaped terpolymers comprised of hydrophobic poly(?‐caprolactone), pH‐sensitive polyaminoester block and hydrophilic poly(ethylene glycol) (M_n = 1100, 2000 g mol^?1) were synthesized using symmetric pentaerythritol as the core initiator for ring‐opening polymerization (ROP) reaction of ?‐caprolactone functionalized with amino ester dendrimer structure at all chain ends. Subsequently, a second ROP reaction was performed by means of four‐arm star‐shaped poly(?‐caprolactone) macromer with eight ‐OH end groups as the macro‐initiator followed by the attachment of a poly(ethylene glycol) block at the end of each chain via a macromolecular coupling reaction. The molecular structures were verified using Fourier transform infrared and ¹H NMR spectroscopies and gel permeation chromatography. The terpolymers easily formed core–shell structural nanoparticles as micelles in aqueous solution which enhanced drug solubility. The hydrodynamic diameter of these agglomerates was found to be 91–104 nm, as measured using dynamic light scattering. The hydrophobic anticancer drug curcumin was loaded effectively into the polymeric micelles. The drug‐loaded nanoparticles were characterized for drug loading content, encapsulation efficiency, drug–polymer interaction and in vitro drug release profiles. Drug release studies showed an initial burst followed by a sustained release of the entrapped drug over a period of 7days at pH = 7.4 and 5.5. The release behaviours from the obtained drug‐loaded nanoparticles indicated that the rate of drug release could be effectively controlled by pH value. Altogether, these results demonstrate that the designed nanoparticles have great potential as hydrophobic drug delivery carriers for cancer therapy. © 2015 Society of Chemical Industry     

In vitro biocompatibility and mucoadhesion of montmorillonite chitosan nanocomposite: A new drug delivery

A “Clay Bio Polymer Nanocomposite” (CBPN) to be used in drug release was prepared by dispersion of montmorillonite (Mt) particles in chitosan (Ch) solution. The obtained hybrid material was characterized for in vitro biocompatibility on Caco-2 cell cultures. Cytotoxicity and cell proliferation of the nanocomposite were tested, comparing results with free Ch and Mt. Cell proliferation was assessed both by WST-1 test and wound-healing measurements by means of Image Analysis Software. The last method is a proof of concept test that has the advantage of direct visualization and quantification of cell growth. Nanocomposite was also characterized for hydration (water uptake) pattern and mucoadhesive properties, which were considered as important features for the application of this material in modified release systems.Results showed that the prepared CBPN showed good biocompatibility in the range 5–500 μg/ml, being also able to effectively stimulate cell proliferation. Moreover, nanocomposite possessed mucoadhesive properties combined with low solubility in acidic environment. We conclude that interaction between Ch and Mt produced a new biohybrid material that can be considered as promising candidate for modified drug delivery formulations.     

Carbohydrate crosslinked biocompatible polyurethanes: Synthesis,characterization, and drug delivery studies

A series of novel polyurethanes (PUs) with carbohydrate crosslinkers was synthesized. The drug loading and release kinetics were studied by using lamotrigine as a model drug. The polymers were designed in such a way that the drug release was tailored by differences in the stoichiometry of polymers. All the PUs were characterized for thermal and morphological properties by using differential scanning calorimetry and thermogravimetric analysis and scanning electron microscope , respectively. The encapsulation of drug inside PU matrix was confirmed via Fourier transform ‐ infrared (FT‐IR) spectra and scanning electron microscope . The kinetics and release mechanisms were observed to be a function of stoichiometric parameters such as type of crosslinker, polyol/crosslinker ratio and polyol/chain extender ratio. All the PUs were observed to be non‐cytotoxic in normal lung cell line L132. The synthesized PUs exhibited good mechanical strength, tunable release rates and biocompatibility that can be utilized in biomedical applications like wound dressing, biomedical implants , and drug delivery carriers. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42223.     

Versatile hybrid polyethyleneimine–mesoporous carbon nanoparticles for targeted delivery

To meet the needs of targeted drug delivery and medical imaging, uniform mesoporous carbon spheres (UMCS) were functionalized using hyperbranched polyethyleneimine (PEI) covalently linked with fluorescein isothiocyanate (FITC) and folic acid (FA). Folate-receptor-positive KB cancer cells internalized five times more nanoparticles than A549 cells deficient in folate receptors in vitro using flow cytometry and confocal microscopy. The in vivo distribution results also confirmed that the FA–PEI–FITC–UMCS nanoparticles could target the FA-positive tumors. In addition, the specifically targeted hybrid carbon nanoparticles exhibited non-cytotoxic and controlled intracellular release (pH dependent) of the loaded agents. The in vivo antitumor effect of the paclitaxel (PTX)-loaded nanoparticles was investigated in Kunming mice harboring a hepatic H22 tumor. PTX-loaded FA–PEI–UMCS nanoparticles displayed superior antitumor effects compared to other PTX formulations, and the tumor growth inhibition rate was 86.53% compared with the control group (saline) for the enhanced targeted accumulation of NPs in tumor cells.     

F3-functionalized nanoscale metal–organic frameworks for tumor-targeting combined chemotherapy and chemodynamic therapy

Nanoscale metal–organic frameworks (nMOFs) have attracted much attention as emerging porous materials as drug delivery carriers. Appropriate surface modification of them can greatly improve stability and introduce biocompatibility and cancer targeting functionality into drug delivery systems. Herein, we prepared nano-sized MIL-101(Fe)-N₃ and loaded anticancer drug doxorubicin (DOX) into it. The synthetic polymer layer Alkyne-PLA-PEG was then attached to the F3 peptide (labeled as Alkyne-PLA-PEG-F3), and the surface of DOX/MIL-101(Fe)-N₃ was covalently modified with it to obtain DOX/MIL-101-PLA-PEG-F3. Nano-sized MIL-101(Fe)-N₃ has high drug loading capacity and the modification of MIL-101(Fe)-N₃ by polymer Alkyne-PLA-PEG not only improved the dispersion, but also avoided the sudden release of the drugs and increased the biocompatibility of nanocarriers. The F3 peptide introduced into the nanocarriers also enabled it to specifically target tumor tissues and achieved active targeted drug delivery. As a nucleolin-mediated endocytosis drug delivery system, DOX/MIL-101-PLA-PEG-F3 can not only deliver anticancer drugs to tumors accurately, but also participate in Fenton-like reaction to generate hydroxyl radicals (•OH) for chemodynamic therapy (CDT), thus enabling combination therapy. It holds great promise as drug candidates to reduce systemic toxicity and improve the efficacy of cancer treatment.     

Depolymerized chitosan nanoparticles for protein delivery: Preparation and characterization

In this article we describe our preliminary work involving the use of depolymerized, low molecular weight chitosan nanoparticles as carriers for proteins and peptides. We hypothesized that the molecular weight of chitosan could favorably modulate the particle and protein release characteristics for the delivery of certain bioactive macromolecules. Our primary objectives were to develop nanoparticle formulations that were stable and reproducible across a range of chitosan molecular weights and then characterize the physicochemical and in vitro release properties as functions of the polymer size. Using depolymerized fragments generated by NaNO₂ degradation of different chitosan salts, we prepared nanoparticle formulations based on ionotropic gelation with sodium tripolyphosphate (TPP). Regardless of the formulation, the nanoparticle size decreased with decreasing molecular weight and the ζ‐potential values remained unchanged. Similar comparisons were made with the encapsulation of insulin and tetanus toxoid as model proteins. The results indicated that the quantity of TPP in a given formulation has a greater effect on the protein encapsulation than the chitosan molecular weight. In fast release environments (i.e., buffered media), there was no significant molecular weight effect that could be discerned. These data lead to the conclusion that, under these experimental conditions, the chitosan molecular weight has a measurable effect on the particle properties, although this effect is modest relative to other formulation parameters (e.g., TPP content, type of protein loaded). Because these subtle differences could have dramatic effects physiologically, work is currently underway to elucidate the possible applications of depolymerized chitosans for peptide delivery in vivo. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 12: 2769–2776, 2003