Paclitaxel release from micro-porous PLGA disks

Micro-porous biodegradable polymeric foams have potential applications in tissue engineering and drug delivery systems. A two-stage fabrication process combining spray drying and supercritical gas foaming is presented for the encapsulation of paclitaxel in micro-porous PLGA (poly lactic glycolic acid) foams. Encapsulation of paclitaxel in the PLGA polymer matrix was achieved and these foams have potential application as a new type of surgical implant for controlled release of paclitaxel. This technique may also be applied to other hydrophobic drugs which face problems of slow release when encapsulated in a compact polymeric device. The micro-porous structure helps to increase drug release rate due to a shorter diffusion path of the drug in the polymer. The final residual organic solvent content in the polymer was low and well within safety limits due to the high miscibility of supercritical CO₂ with the organic solvent. The pore size distribution, the phase behavior, and the in vitro swelling behavior of the foams were characterized. In vitro release results showed a nearly constant release rate for up to 8 weeks. The release profiles from micro-porous foam and from compressed disks were compared to assess the performance of micro-porous foams as sustained release implants. The foams implanted intracranially in mice showed therapeutic concentrations of paclitaxel at distant regions of the brain even after 28 days of implantation.     

Preparation of nanoparticles by the self-organization of polymers consisting of hydrophobic and hydrophilic segments: Potential applications

This review describes the preparation of core-corona type polymeric nanoparticles and their applications in various technological and biomedical fields. Over the past two decades, we have studied the synthesis and clinical applications of core-corona polymeric nanoparticles composed of hydrophobic polystyrene and hydrophilic macromonomers. These nanoparticles were utilized as catalyst carriers, carriers for oral peptide delivery, virus capture agents, and vaccine carriers, and so on. Moreover, based on this research, we attempted to develop novel biodegradable nanoparticles composed of hydrophobic poly(γ-glutamic acid) (γ-PGA) derivatives (γ-hPGA). Various model proteins were efficiently entrapped on/into the nanoparticles under different conditions: encapsulation, covalent immobilization, and physical adsorption. The encapsulation method showed the most promising results for protein loading. It is expected that biodegradable γ-hPGA nanoparticles can encapsulate and immobilize various biomacromolecules. Nanoparticles consisting of hydrophobic and hydrophilic segments have great potential as multifunctional carriers for pharmaceutical and biomedical applications, such as drug, protein, peptide or DNA delivery systems.     

A novel biodegradable amphiphilic diblock copolymers based on poly(lactic acid) and hyaluronic acid as biomaterials for drug delivery

An amphiphilic poly((lactic acid)-b-hyaluronic acid) diblock copolymer, poly(LA-b-HA), was synthesized from short-chain hyaluronic acid and poly(lactic acid). The synthesis was conducted by coupling the N, N′- dicyclohexylcarbodiimide activated poly(lactic acid) to a short-chain hyaluronic acid which was pre-aminated with 1, 2-ethylenediamine at the reducing end followed by NaCNBH₃ reduction. The poly (LA-b-HA) copolymers synthesized were verified by the spectral analyses of FTIR and ¹H NMR. The poly(LA-b-HA) molecules can self-assemble into micelles in aqueous solution. The average diameters of polymeric micelles were estimated to be 116 ± 17 and 98 ± 11 nm for the polymeric micelles derived from the poly(lactic acid)s of MW 3,200 and MW 16,900, respectively. The poly(LA-b-HA) copolymeric material is non-cytotoxic and can be used as micellar drug carriers. The drug encapsulation capabilities of these poly(LA-b-HA) micelles were demonstrated by using ellagic acid and lidocaine chloride as model compounds. These new biodegradable micelles have a great potential to be used as drug delivery carrier for biomedical applications.     

Advances in drug delivery systems based on synthetic poly(hydroxybutyrate) (co)polymers

Within the general context of nanomedicine, drug delivery systems based on polymers have sparked a rapidly growing interest and raised many efforts to tackle various diseases, among which cancer. Polyester-based nanoparticulate drug delivery systems, including polymer-drug conjugates and amphiphilic block copolymers, represent a major class with promising outcomes, especially for those derived from poly(3-hydroxybutyrate) (PHB). This review describes recent advances in drug delivery systems designed from the self-assembly of synthetic (co)polymers derived from PHB. The various strategies for the synthesis of PHB-conjugates, PHB/poly(ethylene glycol) (PEG) and other PHB-based copolymers are first summarized. Nanoparticles, micelles, microparticles, and hydrogels elaborated from these (co)polymers following various preparation methods, along with their exploitation in the encapsulation and release of various therapeutic agents, are next detailed. Finally, we discuss the synthetic challenges, drug delivery outlooks, and perspectives of PHB-based drug delivery systems. Engineered nano-scaled materials based on PHB self-assembled systems are thus anticipated to emerge as a valuable platform for original drug delivery systems.     

Micelles formed by self‐assembly of hyperbranched poly[(amine‐ester)‐co‐(D,L‐lactide)] (HPAE‐co‐PLA) copolymers for protein drug delivery

BACKGROUND: The aim of the work presented was to synthesize a series of amphiphilic hyperbranched poly[(amine‐ester)‐co‐(D ,L ‐lactide)] (HPAE‐co‐PLA) copolymers and study the formation of copolymeric micelles. These copolymeric micelle systems are expected to be potential candidates for applications in protein drug delivery. RESULTS: The chemical structures of the copolymers were confirmed by Fourier transform infrared spectroscopy, ¹³C NMR and thermogravimetric analysis. Fluorescence spectroscopy and dynamic light scattering confirmed the formation of copolymeric micelles of the HPAE‐co‐PLA copolymers. The maintenance of stability of bovine serum albumin (BSA) during release from micelles in vitro was also measured using circular dichroism and fluorescence spectrometry. CONCLUSION: Novel hyperbranched HPAE‐co‐PLA copolymers have been synthesized. Conjugation of PLA to HPAE was proved to be an available method for the preparation of micelles for protein delivery. The BSA‐loaded micelles showed enhanced encapsulation efficiency and the structural stability of BSA was retained during the release process. The hyperbranched polymeric micelles could be useful as drug carriers for protein drug delivery systems. Copyright © 2008 Society of Chemical Industry     

Nanoparticles composed of PLGA and hyperbranched poly (amine-ester) as a drug carrier

A new hyperbranched poly (amine-ester)-poly (lactide-co-glycolide) (HPAE-co-PLGA) copolymer was synthesized by ring-opening polymerization of D, L-lactide, glycolide and a fourth generation branched poly (amine-ester) (HPAE-OHs4) with Sn(Oct)₂ as catalyst. The chemical structures of copolymers were determined by FT-IR, ¹H-NMR (¹³C NMR), TGA and their molecular weights were determined by gel permeation chromatography (GPC). Two methods, double emulsion (DE) and nanoprecipitation (NP), were employed to fabricate the polymeric nanoparticles. Isoniazid (INH) was loaded as a model antitubercular drug. Influence of the preparation conditions on the nanoparticles size, encapsulation efficiency and release profile in vitro was investigated. Their entrapment efficiency (EE) to INH could reach 96% at an available condition. In vitro release behavior of NPs showed a continuous release after a burst release. The results showed that the HPAE-co-PLGA copolymer nanoparticles have a promising potential in hydrophilic drug delivery system.     

Modification of hydrophilic polymer network to design a carrier for a poorly water-soluble substance

pH sensitive, nontoxic, and biocompatible poly(methacrylic) acid (PMAA) based soft networks have been extensively used in the design of systems for targeted drug delivery. Still, their highly hydrophilic nature limits their potential to be used as a carrier of poorly water-soluble substances. With the aim to overcome this limitation, the present study details a new approach for modification of PMAA based carriers using two amphiphilic components: casein and liposomes. The FTIR analysis revealed structural features of each component as well as the synergetic effect that originated from the formation of specific interactions. Namely, hydrophobic interactions between the poorly water-soluble model drug (caffeine) and casein enabled caffeine encapsulation and controlled release, while addition of liposomes ensured better control of the release rate. The morphological properties of the carriers, swelling behavior, and release kinetics of caffeine were investigated depending on the variable synthesis parameters (neutralization degree of methacrylic acid, concentration of caffeine, presence/absence of liposomes) in two different media simulating the pH environment of human intestines and stomach. The data obtained from in vitro caffeine release were correlated and analyzed in detail using several mathematical models, indicating significant potential of investigated carriers for targeted delivery and controlled release of poorly water-soluble substances.     

离子液体中ATRP合成MCC-g-PMAA及其分子对阿司匹林控释的应用

以离子液体氯化1-烯丙基-3-甲基咪唑（[Amim]Cl）为反应介质,利用原子转移自由基聚合（atom transfer radical polymerization,ATRP）法合成了微晶纤维素接枝有聚甲基丙烯酸（MCC-g-PMAA）的pH敏感性聚合物。用透析法将模型药物阿司匹林包覆在聚合物胶束内,并对载药胶束的体外药物释放机制进行研究。通过红外、核磁、透射电镜、X射线衍射和紫外分光光度计等分析手段对聚合物的结构、胶束形貌、胶束对阿司匹林的载药性能及释药性能进行了表征分析。结果表明：聚合物胶束能够在水溶液中自组装成球状胶束,对阿司匹林具有良好的包载效果,阿司匹林在碱性条件下的累积释放量大于酸性条件,载药胶束表现出了良好的pH敏感性和药物缓释性能。     

Preparation and Evaluation of Poly(Ethylene Glycol)–Poly(Lactide) Micelles as Nanocarriers for Oral Delivery of Cyclosporine A

A series of monomethoxy poly(ethylene glycol)–poly(lactide) (mPEG–PLA) diblock copolymers were designed according to polymer–drug compatibility and synthesized, and mPEG–PLA micelle was fabricated and used as a nanocarrier for solubilization and oral delivery of Cyclosporine A (CyA). CyA was efficiently encapsulated into the micelles with nanoscaled diameter ranged from 60 to 96 nm with a narrow size distribution. The favorable stabilities of CyA-loaded polymeric micelles were observed in simulated gastric and intestinal fluids. The in vitro drug release investigation demonstrated that drug release was retarded by polymeric micelles. The enhanced intestinal absorption of CyA-loaded polymeric micelles, which was comparable to the commercial formulation of CyA (Sandimmun Neoral®), was found. These suggested that polymeric micelles might be an effective nanocarrier for solubilization of poorly soluble CyA and further improving oral absorption of the drug.     

Enhanced therapeutic efficacy of clotrimazole by delivery through poly(ethylene oxide)-block-poly(ε-caprolactone) copolymer-based micelles

Amphiphilic block copolymers have been the subject of great scientific interests due to their applications in various fields including nano drug delivery. Three amphiphilic block copolymers based on poly(ε-caprolactone) as a hydrophobic segment and methoxy poly(ethylene oxide) ( as a hydrophilic part were synthesized by the ring-opening polymerization of ε-caprolactone using MeO-PEO_5K as macroinitiator by varying initial feed ratios. The synthesized polymers were further explored for their drug delivery potential using clotrimazole as model hydrophobic drug. Drug-loaded micelles were characterized for shape, size, drug encapsulation efficiency, in vitro release, and thermal stability using atomic force microscope, zetasizer, UV–visible spectrophotometry, FTIR, differential scanning calorimetry, and thermogravimetric analysis. Clotrimazole loaded in micelles were also investigated for its antifungal activity through an in vitro assay and scanning electron microscopy. The antifungal activity of drug increased significantly by delivering through polymeric micelles. Current study provides insight into different factors that can be maneuvered to achieve a variety of desired properties of micelles for improved therapeutic efficacy of drugs like clotrimazole. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47769.     

Swelling and drug release profile of poly(2‐ethyl‐2‐oxazoline)‐based hydrogels prepared by gamma radiation‐induced copolymerization

Poly(2‐ethyl‐2‐oxazoline) and acrylic acid were copolymerized in different compositions using γ‐rays‐induced polymerization and cross‐linking to obtain a series of pH‐sensitive hydrogels. The preparation parameters that may affect the copolymerization process such as the feed solution composition and irradiation dose were optimized. Swelling characteristics of the obtained polymeric hydrogels were evaluated. The results show the significant effects of the hydrogel composition, soaking time, and pH on the swelling equilibrium. The diffusion parameters obtained at pH 1 and 7 show the possibility of using the prepared hydrogels in the field of colon‐specific drug delivery systems. Ibuprofen as a model drug was loaded into (poly(2‐ethyl‐2‐oxazoline)/acrylic acid) copolymer hydrogel to investigate their drug release behavior at different pH values. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

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     

Improving anti-tumor activity with polymeric micelles entrapping paclitaxel in pulmonary carcinoma

Nanoscale polymeric micelles have promising applications as drug delivery systems (DDS). In this work, to improve the anti-tumor activity and eliminate toxicity of the commercial formulation (cremophor EL and ethanol) of paclitaxel (PTX), we developed biodegradable poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles entrapping PTX by a simple one-step solid dispersion method, which is without any surfactants or additives and is easy to scale up. In addition, the PTX micelles could be lyophilized into powder without any adjuvant and the re-dissolved PTX micelles are stable and homogeneous. The prepared PTX micelles have a mean particle size of 38.06 ± 2.30 nm, a polydispersity index of 0.168 ± 0.014, a drug loading of 14.89 ± 0.06% and an encapsulation efficiency of 99.25 ± 0.38%. A molecular modeling study implied that PTX interacted with PCL as a core, which was embraced by PEG as a shell. The encapsulation of PTX in polymeric micelles enhanced its cytotoxicity by increasing the uptake by LL/2 cells. A sustained in vitro release behavior and slow extravasation behavior from blood vessels in a transgenic zebrafish model were observed in the PTX micelles. Furthermore, compared with Taxol?, the PTX micelles were more effective in suppressing tumor growth in the subcutaneous LL/2 tumor model. The PTX micelles also inhibited metastases in the pulmonary metastatic LL/2 tumor model and prolonged survival in both mouse models. Pharmacokinetic and tissue distribution studies showed that after PTX was encapsulated in polymeric micelles, the biodistribution pattern of PTX was altered and the PTX concentration in tumors was increased compared with Taxol? after intravenous injection. In conclusion, we have developed a polymeric micelles entrapping PTX that enhanced cytotoxicity in vitro and improved anti-tumor activity in vivo with low systemic toxicity on pulmonary carcinoma. The biodegradable MPEG-PCL micelles entrapping PTX may have promising applications in pulmonary carcinoma therapy.     

Tamoxifen‐loaded microspheres based on mixtures of poly(D,L‐lactide‐co‐glycolide) and poly(D,L‐lactide) polymers: Effect of polymeric composition on drug release and in vitro antitumoral activity

Mixtures of different bioerosionable polyesters were used to prepare microparticulated tamoxifen delivery systems to achieve anticancer effects in breast malignant cancer cells. Tamoxifen (TMX) was included into microspheres (MS) formulated via spray‐drying. Mixtures of poly(D ,L ‐lactide‐co‐glycolide) (PLGA) of different lactide/glycolide proportions (50 : 50 and 75 : 25) and poly(D ,L ‐lactic acid) (PLA) were used. The average diameter of the resultant TMX‐loaded microparticles was in the range 1.04 ± 0.51–1.55 ± 0.95 μm. The encapsulation efficiency of TMX was between 97.8% [48.9 ± 0.1 TMX (μg)/MS (mg)] and 69.6% [36.6 ± 0.1 TMX (μg)/MS (mg)] depending on the polymeric composition of the formulation. Drug burst effect was not observed. TMX was released from the polymeric matrices in a sustained release manner between 11 and 58 days depending on polymeric composition of microspheres. TMX‐loaded microspheres showed high efficacy in causing cell death in MCF7 breast malignant cancer cells. Thus, these TMX‐loaded PLGA‐based microspheres hold potential to treat breast malignant cancer cells. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Novel strategy for encapsulation and targeted delivery of poorly water-soluble active substances

Carriers for targeted delivery and controlled release of poorly water-soluble active substances (PWSAS) are facing three challenges: (a) the encapsulation issues, (b) limitations of PWSAS water solubility, and (c) burst drug release which can be pharmacologically dangerous and economically inefficient. The present study brings a novel strategy for encapsulation and controlled release of PWSAS—caffeine in concentrations which are higher than its maximal water solubility without the possibility of burst effect. The modification of hydrophilic carrier based on poly(methacylic acid) was done using casein and liposomes. To further increase the maximal caffeine loading inside the carrier nicotinamide was used. The release study of the encapsulated PWSAS was elaborated with respect to morphology of the carriers and interactions that could be established between its structural components. The carriers swelling and the release of caffeine and nicotinamide were also investigated depending on caffeine concentration, the presence of different liposomal formulations and the volume ratio of liposomal formulation, in three media with different pH simulating the path of the carrier through the human gastrointestinal tract. The synthesized carriers are promising candidates for encapsulation of PWSAS in concentrations which are higher than its maximal water solubility and for the targeted delivery of those dosages.     

Pasty Polymers in Cancer Drug Therapy

Injectable polymeric systems suitable for the localized delivery of anticancer agents are reviewed. These polymeric systems include: drug-loaded low melting temperature polymers that are injected at the melting temperature of the polymer, usually below 50 °C, that solidify at body temperature to form an in situ device; polymer solutions in buffer or in N-methyl pyrrolidone, ethanol, or acetate esters which, upon injection in tissue,are absorbed into the tissue and cause precipitation of the polymer at the injection site; in situ crosslinking of polymer solutions to form a polymeric implant; and thermoresponsive polymer solutions that are soluble at room temperature and solidify at body temperature. However, these systems are hydrophilic and suffer from burst release of drug within a few hours post injection. Hydrophobic injectable, pasty, fat-based polymers that gel when injected in tissue have been used for the extended release of paclitaxel, cisplatin, and other agents. This polymer releases the drug in a controlled manner with no burst release. These systems have a potential use as drug carriers for regional or systemic drug delivery.     

Dual-sensitive and folate-conjugated mixed polymeric micelles for controlled and targeted drug delivery

For this study, we prepared a new type of drug carrier with the characteristics of stimuli-responsive transition and tumor-specific recognition through the co-assembly of two series of amphiphilic block copolymers, poly(ε-caprolactone)-b-poly[triethylene glycol methacrylate-co-N-methacryloyl caproic acid] and poly(ε-caprolactone)-b-poly[triethylene glycol methacrylate-co-N-(2-(methacrylamido)ethyl) folatic amide]. The pH-dependent thermal transition and the content of the targeting ligands of the mixed polymeric micelles are well correlated with the chemical structures and compositions of these two copolymers. Doxorubicin-loaded mixed polymeric micelles are stable at body temperature in the neutral condition for prolonged circulation in blood vessels, and demonstrated rapid drug release at acidic pH levels. The cumulative drug release profiles showed a relatively slow release at pH 7.4, and a quick release of 85% in 3 h at pH 5.3. The cytotoxicity tests against FA-positive (HeLa) and FA-negative (HT-29) tumor cell lines suggest that this mixed polymeric micelle system has potential merits as a controlled and targeted drug delivery system.     

Formulating Drug Delivery Systems by Spray Drying

The knowledge of the potential use of the spray-drying technology to prepare microparticulate drug delivery systems—microspheres and microcapsules—has been strongly improved over the last years. Various microparticulate spray drying systems used as vehicles for drug encapsulation and delivery that have been investigated for different purposes are presented here, including spray-dried powders formulated with hydrophilic polymers allowing controlled drug release, biodegradable microspheres prepared from aqueous systems, and spray-dried silica gel microspheres.     

Amphiphilic core-shell nanoparticles with dimer fatty acid-based aliphatic polyester core and zwitterionic poly(sulfobetaine) shell for controlled delivery of curcumin

Multifunctional nanocarriers are gaining increasing research interest as polymeric platforms for targeted drug delivery in cancer therapy and diagnosis. In this work, preparation and characterization of surfactant-free polyester nanoparticles (NPs) from a bio-based poly(butylene sebacate-co-butylene dilinoleate)s, poly(butylene sebacate) (PBSE)/poly(butylene dilinoleate) (PBDL), using nanoprecipitation, is reported. The polymeric nanoparticles (sizes narrowly distributed in a range less than 100?nm) were loaded with curcumin (CURC) with an encapsulation efficiency of 98% and drug loading (DL) content of 5–10% wt_drug/wt_polymer. The CURC-loaded nanoparticles were efficiently coated with a novel poly(sulfobetaine)-type zwitterionic polymer synthesized by nitroxide-mediated polymerization and postpolymerization functionalization step. Free and CURC formulated into noncoated and poly(sulfobetaine)-type zwitterionic polymer-coated nanoparticles were further investigated for cytotoxicity and antioxidant activity in a panel of human cell lines and rat liver microsomes, respectively. Formulated into coated NPs, CURC has superior cytotoxic and antioxidant activity versus the free drug and CURC incorporated in noncoated NPs. In addition, cell viability experiments of nonloaded nanoparticles, both coated and noncoated, demonstrated that developed nanoparticles are nontoxic, making them potentially suitable candidates for systemic passive targeting in cancer therapy, namely for treatment of solid tumors exhibiting high tumor accumulation of NPs due to enhanced permeability and retention effect. Polyzwitterion-coated nanoparticles exhibited slower drug release compared with the noncoated ones (half as much after 24?h) presumably due to the presence of the polymer shell around nanoparticles associated with a wider diffusion layer around the particles.     

Stimuli-responsive hybrid microgels for controlled drug delivery: Sorafenib as a model drug

Microgels (MGs) are synthetic colloidal hydrogel particles made of three dimensional polymer networks. Their chemical composition is crucial for their use as intelligent drug release systems operated by temperature control. Herein, several MGs using N-isopropylacrylamide (Nipam)/N-isopropylmethacrylamide (Nipmam), chitosan and acrylic/methacrylic acid have been synthesized by free radical polymerization reactions (NC MGs) and the effects of surfactants and different reaction times on size and swelling properties have been investigated. MGs have been identified and characterized by dynamic light scattering and atomic force microscopy, and finally used to optimize the encapsulation protocol of the hydrophobic drug sorafenib. The drug delivery system here described has encapsulation efficiency of 40% and releases 10% of the entrapped drug over about 16 h after the temperature is raised above the volume phase transition temperature. Data suggest that MGs with optimized composition may act as properly instructed entities able to trap and release biomolecules following external stimuli.