Synthesis and Characterization of Novel Amphiphilic Polymers as Drug Delivery Nano Carriers

Polymer nano-particles have been widely investigated in the last decade due to a variety of potential applications. In particular, polymers which can self assemble into micellar nano-particles can be effectively used as vehicles for drug delivery. Considerable efforts are underway to develop better drug delivery nano carriers for high drug loading capacity for a wide variety of bioactive compounds. In this study, several new polymers were synthesized in bulk (solventless condition) by a chemo-enzymatic methodology using Candida antarctica lipase B (Novozyme 435) and molecular sieves (MS). The synthesized polymers demonstrated high drug loading capacity and the potential to encapsulate drugs which are poorly soluble in aqueous solvents.     

Amino Acid and Poly(Ethylene Glycol) Based Self-Organizing Polymeric Systems: Chemo-Enzymatic Synthesis and Characterization

A chemo/regio selective enzymatic methodology has been designed to synthesize amphiphilic copolymers based on amino acid diesters and poly(ethylene glycol) [PEG]. The condensation polymerization was catalyzed by immobilized Candida antarctica lipase B (Novozyme 435) under solvent-less conditions. The synthesized polymers 3a–c were derivatized with long chain acid chlorides by chemical acylation to get the amphiphilic polymers 4a–c. The physical properties of the synthesized amphiphilic polymers viz: aggregation number, critical micelle concentration (CMC), radius of gyration (R_g), hydrodynamic radius (R_h) and particle size distribution were studied by static and dynamic light scattering (SLS and DLS) techniques. The polymers were found to be promising in drug delivery applications.     

Molecular Imprinted Polymers for use as Drug Delivery Devices: Preliminary Evaluation

In view of technological significance of molecular imprinting polymers in drug delivery, the present study is an attempt to synthesize 2‐hydroxyethylmetacrylate (HEMA) and acrylic acid (AAc) based hydrogels imprinted with model drug glucose. Both molecular imprinted polymers (MIPs) and non‐imprinted polymers (NIPs) have been synthesized and have been used to study their binding affinity, swelling and in vitro release dynamics of the drug. It has been observed from this study that the template formed in MIPs has increased the absorption percentage of the drug and has improved the release profile of the drug from these polymers.     

Design and Synthesis of ZnII‐Coordination Polymers Anchored with NSAIDs: Metallovesicle Formation and Multi‐drug Delivery

A series of coordination polymers synthesized from a bis‐pyridyl linker, namely 4,4′‐azopyridine ( L ), selected non‐steroidal‐anti‐inflammatory drugs (NSAIDs), namely diclofenac ( Dic ), ibuprofen ( Ibu ), flurbiprofen ( Flu ), mefenamic acid ( Mefe ), and naproxen ( Nap ), and Zn(NO₃)₂ were characterized by single crystal X‐ray diffraction. One of the coordination polymers, namely CP3 derived from Flu , was able to form metallovesicles in DMSO, DMSO/H₂O and DMSO/DMEM (biological media) as revealed by TEM, AFM and DLS. Metallovesicle formation by CP3 was further supported by loading a fluorescent dye, namely calcein, as well as an anti‐cancer drug, doxorubicin hydrochloride ( DOX ), as revealed by UV‐vis and emission spectra, and fluorescence microscopy. DOX ‐loaded metallovesicles of CP3 ( DOX@CP3‐vesicle ) could be delivered in vitro to a highly aggressive human breast cancer cell line, namely MDA‐MB‐231, as revealed by MTT and cell migration assays, and also cell imaging performed under laser scanning confocal microscope (LSCM). Thus, a proof of concept for developing a multi‐drug delivery system derived from a metallovesicle for delivering an anti‐cancer drug to cancer cells is demonstrated for the first time.     

Thermosensitive and photocleavable polyaspartamide derivatives for drug delivery

The development of novel thermo‐ and photo‐dual‐responsive biodegradable polymeric micelles based on amphiphilic polyaspartamide derivatives (NB‐g‐PHPA‐g‐mPEG) for anticancer drug delivery is reported. The obtained polymers containing hydrophobic photocleavable o‐nitrobenzyl groups exhibit thermo‐ and photosensitivity. The micelles and paclitaxel‐loaded micelles based on the thermo‐ and photo‐dual‐sensitive polymers were prepared by a quick heating method without using toxic organic solvent. The paclitaxel release from the drug‐loaded micelles can be triggered under photoirradiation. Enhancement of the anticancer activity against HeLa cells was observed for paclitaxel‐loaded NB‐g‐PHPA‐g‐mPEG micelles after light irradiation, while the empty NB‐g‐PHPA‐g‐mPEG micelles with or without irradiation did not show any toxicity. Therefore, the thermo‐ and photo‐dual‐responsive NB‐g‐PHPA‐g‐mPEG micelles have a promising future applied as a light controlled drug delivery system for anticancer drugs. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 2855–2863     

Synthesis and characterization of poly-α,β-[N-(2-hydroxyethyl)-L-aspartamide]-g-poly(glycolide) amphiphilic graft copolymers as potential drug carriers

A series of biodegradable amphiphilic graft polymers were successfully synthesized by grafting poly(glycolide) (PGA) sequences onto a water-soluble poly-α,β-[N-(2-hydroxyethyl)-_L-aspartamide] (PHEA) backbone. These novel graft polymers were synthesized by the ring-opening polymerization initiated by the macroinitiator PHEA bearing hydroxyl groups without adding any catalyst. The graft polymers were characterized by Fourier transform infrared spectroscopy (FTIR), ¹H nuclear magnetic resonance spectroscopy (¹H NMR), combined size-exclusion chromatography (SEC) and multiangle laser light scattering (MALLS) analysis, and differential scanning calorimetry (DSC). By controlling the feed ratio of the macroinitiator to the monomer, graft polymers with different branch lengths can be obtained. The degradation behaviors of the copolymers were studied. Based on the amphiphilicity of the graft copolymers, nanoparticle drug delivery systems were prepared by the direct dissolution method and the dialysis method, and the in vitro drug release behavior was investigated. Transmission electron microscopy (TEM) images demonstrated that these nanoparticles were regularly spherical in shape. The particle size and distribution of the nanoparticles were measured.     

Synthesis and characterization of a multiarm poly(acrylic acid) star polymer for application in sustained delivery of cisplatin and a nitric oxide prodrug

Functionalized polymeric nanocarriers have been recognized as drug delivery platforms for delivering therapeutic concentrations of chemotherapies. Of this category, star‐shaped multiarm polymers are emerging candidates for targeted delivery of anticancer drugs, due to their compact structure, narrow size distribution, large surface area, and high water solubility. In this study, we synthesized a multiarm poly(acrylic acid) star polymer via macromolecular design via the interchange (MADIX)/reversible addition fragmentation chain transfer (MADIX/RAFT) polymerization and characterized it using nuclear magnetic resonance (NMR) and size exclusion chromatography. The poly(acrylic acid) star polymer demonstrated excellent water solubility and extremely low viscosity, making it highly suited for targeted drug delivery. Subsequently, we selected a hydrophilic drug, cisplatin, and a hydrophobic nitric oxide (NO)‐donating prodrug, O²‐(2,4‐dinitrophenyl) 1‐[4‐(2‐hydroxy)ethyl]‐3‐methylpiperazin‐1‐yl]diazen‐1‐ium‐1,2‐diolate, as two model compounds to evaluate the feasibility of using poly(acrylic acid) star polymers for the delivery of chemotherapeutics. After synthesizing and characterizing two poly(acrylic acid) star polymer‐based nanoconjugates, poly(acrylic acid)–cisplatin (acid–Pt) and poly(acrylic acid–NO (acid–NO) prodrug, the in vitro drug release kinetics of both the acid–Pt and the acid–NO were determined at physiological conditions. In summary, we have designed and evaluated a polymeric nanocarrier for sustained‐delivery of chemotherapies, either as a single treatment or a combination therapy regimen. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

The screening and evaluating of chitosan/β-cyclodextrin nanoparticles for effective delivery mitoxantrone hydrochloride

The complex of chitosan and β-cyclodextrin (CS-CMβ-CD) has been widely used as drug carrier because it binds the advantages of GCH and β-CDs. But further investigation is still needed to improve their delivery performance before CS-β-CD derivatives can be used as clinical cancer-drug carriers. The aim of the study is to screen suitable carriers of the deviants of chitosan and β-cyclodextrin by evaluating the delivery performance of several carriers towards anticancer drugs. Three kinds of GCS _n -CM _m β-CD polymers made of different amount of glycol chitosan (GCS) and carboxymethyl-β-cyclodextrin (CMβ-CD) were synthesized and GCS_7.5-CM_3-7β-CD was chosen to deliver the drugs due to its better properties. GCS_7.5-CM_3-7β-CD polymers have better cell adhesion performance than GCS, help to directional drug delivery. Then, mitoxantrone hydrochloride (MAH) was used as a model drug to evaluate the loading and releasing properties of GCS_7.5-CM_3-7β-CD polymers. GCS_7.5-CM_3-7β-CD polymers could encapsulate MAH with higher loading efficiency and provide pH sensitive MAH release. The amount of MAH released in acidic medium (pH 5.0) was greater than that in weakly basic medium (pH 7.4). The MAH-loaded nanoparticles shows similar inhibition ability as free MAH to HCT116 cell lines, indicate that MAH can be release from the carrier and kill the cancer cells. In addition, the blank GCS_7.5-CM_3-7β-CD nanoparticles show good biocompatibility to the cell. That is to say, GCS_7.5-CM_3-7β-CD polymers not only have the ability to targeting drug delivery but also can realize pH sensitive release, which make them perspective in cancer pharmaceutical application.     

Synthesis of Highly pH‐Responsive Glucose Poly(orthoester)

pH‐Responsive polymers have great potential in biomedical applications, including the selective delivery of preloaded drugs to tissues with low pH values. These polymers usually contain acid‐labile linkages such as esters and acetals/ketals. However, these linkages are only mildly pH‐responsive with relatively long half‐lives (t_1/2). Orthoester linkages are more acid‐labile, but current methods suffer from synthetic challenges and are limited to the availability of monomers. To address these limitations, a sugar poly(orthoester) was synthesized as a highly pH‐responsive polymer. The synthesis was achieved by using 2,3,4‐tri‐O‐acetyl‐α‐D ‐glucopyranosyl bromide as a difunctional AB monomer and tetra‐n‐butylammonium iodide (TBAI) as an effective promoter. Under optimal conditions, polymers with molecular weights of 6.9 kDa were synthesized in a polycondensation manner. The synthesized glucose poly(orthoester), wherein all sugar units were connected through orthoester linkages, was highly pH‐responsive with a half‐life of 0.9, 0.6, and 0.2 hours at pH 6, 5, and 4, respectively.     

pH‐ and β‐cyclodextrin‐responsive micelles based on polyaspartamide derivatives as drug carrier

A novel kind of graft polymer poly(aspartic acid)‐ethanediamine‐g‐adamantane/methyloxy polyethylene glycol (Pasp‐EDA‐g‐Ad/mPEG) was designed and synthesized for drug delivery in this study. The chemical structure of the prepared polymer was confirmed by proton NMR. The obtained polymer can self‐assemble into micelles which were stable under a physiological environment and displayed pH‐ and β‐cyclodextrin (β‐CD)‐responsive behaviors because of the acid‐labile benzoic imine linkage and hydrophobic adamantine groups in the side chains of the polymer. The doxorubicin (Dox)‐loaded micelles showed a slow release under physiological conditions and a rapid release after exposure to weakly acidic or β‐CD environment. The in vitro cytotoxicity results suggested that the polymer was good at biocompatibility and could remain Dox biologically active. Hence, the Pasp‐EDA‐g‐Ad/mPEG micelles may be applied as promising controlled drug delivery system for hydrophobic antitumor drugs. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1387–1395     

Amphiphilic azopolymers capable to generate photo-sensitive micelles

Amphiphilic macromolecular micelles are advantageous for drug delivery applications due to the decrease of side-effects, ease of screening drugs against degradation, long-term stability, targeted delivery and control of the amount of the released drug. A series of amphiphilic azo-polymers having a flexible or rigid main-chain were synthesized and characterized. The presence of chlorobenzyl side-groups allowed both the easy bonding of photo-sensitive or hydrophilic groups and good control of the degree of substitution. The chemical structure was confirmed by ¹H-NMR. The critical concentration of aggregation (CCA) was calculated using the fluorescence emission spectrum of pyrene. The interest was focused on a preliminary study concerning the disaggregation capacity of micelles under UV irradiation. The presence of micellar aggregates was confirmed by DLS and SEM and different organization of the amphiphilic polymers was evidenced depending on polymers concentration and polymers structure. In low polymer concentrations in water predominantly globular aggregates were formed. The increase in concentration increased the polydispersity index due to the fusion of micelles and formation of associates of globular aggregates, inter-micellar associates (clusters) and vesicles.      

Photo-responsive nanoparticles for β-lapachone delivery in vitro

We reported a one-step encapsulation of indocyanine green (ICG) in ZIF-8 nanoparticles (NPs). The as-prepared ICG@ZIF-8 NPs possess an absorption band in the near infrared region and have the good photothermal conversion efficiency.     

Synthesis of Cyclodextrin and Sugar-Based Oligomers for the Efavirenz Drug Delivery

Summary: In the present work water-soluble lactose based oligomers of β-cyclodextrin were synthesized by a simple and efficient condensation polymerization process. Proposed water-soluble β-cyclodextrin oligomers were prepared by controlled reaction between β-cyclodextrin and a triazine linker and purification by an ultrafiltration process. Similarly, lactose based β-cyclodextrin oligomers were synthesized for enhanced water solubility. The physical and chemical properties of the synthesized polymers were characterized by FT-IR and ¹H NMR spectroscopy, XRD analysis, thermogravimetric analysis (TGA) and aqueous solubility determination.. Molecular weights of these β-cyclodextrin based oligomers were measured by ESI technique. These β-cyclodextrin based water-soluble oligomers polymers were used as supramolecular carriers for efavirenz (an anti HIV drug), improving the inclusion property and aqueous solubility properties of this drug. These synthesized oligomers were found to improve stability and aqueous solubility of efavirenz on their (1:1) inclusion complex through phase solubility and dissolution studies. Reduced cytotoxicity than the parent β-CD was observed in hemolysis test.     

聚[碳酸(亚丁酯-co-ε-己内酯)酯]的制备及其载药微球性能的研究

采用阴离子配位聚合方法, 合成了二氧化碳、1,2-环氧丁烷与ε-己内酯的三元共聚物: 聚[碳酸(亚丁酯-co-ε-己内酯)酯](PBCL). 并采用复相乳液(W/O/W)溶剂挥发法制备了包裹抗菌药物甲磺酸帕珠沙星的可降解微球. 对聚合物进行了FTIR, ¹H NMR, ¹³C NMR, DSC, TGA和WAXD等表征, 以及降解性能和载药微球特性的研究. 结果表明, PBCL热稳定性及降解性能优于聚碳酸亚丁酯(PBC). 所得PBCL微球球形规整、表面光滑. 大部分微球粒径在0.5～1 μm的范围内, 载药量和包封率分别达到38.21%和87.9%. 微球的体外释药性能研究在pH 7.4的磷酸缓冲溶液中进行, 释放21 d后, PBCL微球的累积释药量为84.74%, PBC微球的释药量仅为17.29%. 药物的体外释放行为符合Higuchi方程. PBCL载药微球具有长效缓释作用.     

Effects of polymer molecular weight on in vitro and in vivo performance of nanoparticle drug carriers for lymphoma therapy

The clinical efficacy of chemotherapeutic drugs is hindered by their poor aqueous solubility, low bioavailability and severe side effects. In recent years, polymeric nanocarriers have been used for drug delivery to improve the efficacy of many chemotherapeutics. In this study, a series of biodegradable phenylalanine-based poly(ester amide) (Phe-PEA) with tunable molecular weights (MWs) were synthesized to systematically investigate the relationship between the polymer MW and the efficacy of the corresponding polymeric nanoparticles (NPs). The results indicated that a range of polymers with different MWs can be obtained by varying the monomer ratio or reaction time. Doxorubicin (DOX), a classic clinical lymphoma treatment strategy, was selected as a model drug. The loading capacity and stability of the higher MW polymeric NPs were superior to those of the lower MW ones. Moreover, in vitro and in vivo data revealed that high MW polymeric NPs had better anticancer efficacy against lymphoma and higher biosafety than low MW polymeric nanoparticles and DOX. Therefore, this study suggests the importance of polymer MW for drug delivery systems and provides valuable guidance for the design of enhanced polymeric drug carriers for lymphoma treatment.     

Synthesis and properties of amphoteric copolymer of 5‐vinyltetrazole and vinylbenzyl phosphonic acid

Amphoteric polymers have been studied for various applications such as separation of low molecular weight organic molecules from inorganic salt mixtures, selective ion transport, drug delivery through membranes of biological interest, separation of ionic drugs and proteins, and separation of alcohol and water. Typical amphoteric polymers consist of weak base and weak acid groups. In present study, the copolymerization of 5‐vinyltetrazole (VT) and diisopropyl‐p‐vinylbenzyl phosphate (DIPVBP) via free radical polymerization is studied. The reactivity ratio of VT and DIPVBP, which is calculated from Kelen‐Tudos plot, is 0.251 and 0.345, respectively. The amphoteric copolymer of VT and diisopropyl‐p‐vinylbenzyl phosphonic acid (poly(VT‐co‐VBPA)) is obtained from hydrolysis of the copolymer of VT and DIPVBP (poly(VT‐co‐DIPVBP)). Poly(VT‐co‐VBPA) is thermally stable under 190 °C. The anhydrous proton conductivity of amphoteric poly(VT‐co‐VBPA) can reach 1.54 × 10^‐4 S cm^?1 at 170 °C with an activation energy of 114.7 kJ mol^?1. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 3486–3493     

Synthesis of linear and star‐like poly(ε‐caprolactone)‐b‐poly{γ‐2‐[2‐(2‐methoxy‐ethoxy)ethoxy]ethoxy‐ε‐caprolactone} amphiphilic block copolymers using zinc undecylenate

Linear and star‐like amphiphilic diblock copolymers were synthesized by the ring‐opening polymerization of ε‐caprolactone and γ‐2‐[2‐(2‐methoxyethoxy)ethoxy]ethoxy‐ε‐caprolactone monomers using zinc undecylenate as a catalyst. These polymers have potential applications as micellar drug delivery vehicles, therefore the properties of the linear and 4‐arm star‐like structures were examined in terms of their molecular weight, viscosity, thermodynamic stability, size, morphology, and drug loading capacity. Both the star‐like and linear block copolymers showed good thermodynamic stability and degradability. However, the star‐like polymers were shown to have increased stability at lower concentrations with a critical micelle concentration (CMC) of 5.62 × 10^?4 g L^?1, which is less than half the concentration of linear polymer needed to form micelles. The star‐like polymeric micelles showed smaller sizes when compared with their linear counterparts and a higher drug loading capacity of doxorubicin, making them better suited for drug delivery purposes. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3601–3608     

Iron transport-mediated drug delivery using mixed-ligand siderophore-β-lactam conjugates

background: Assimilation of iron is essential for microbial growth. Most microbes synthesize and excrete low molecular weight iron chelators called siderophores to sequester and deliver iron by active transport processes. Specific outer membrane proteins recognize, bind and initiate transport of species-selective ferric siderophore complexes. Organisms most often have specific receptors for multiple types of siderophores, presumably to ensure adequate acquisition of the iron that is essential for their growth. Conjugation of drugs to synthetic hydroxamate or catechol siderophore components can facilitate active iron-transport-mediated drug delivery. While resistance to the siderophore—drug conjugates frequently occurs by selection of mutants deficient in the corresponding siderophore-selective outer membrane receptor, the mutants are less able to survive under iron-deficient conditions and in vivo. We anticipated that synthesis of mixed ligand siderophore—drug conjugates would allow active drug delivery by multiple iron receptor recognition and transport processes, further reducing the likelihood that resistant mutants would be viable.Results: Mixed ligand siderophore-drug conjugates were synthesized by combining hydroxamate and catechol components in a single compound that could chelate iron, and that also contained a covalent linkage to carbacephalosporins, as representative drugs. The new conjugates appear to be assimilated by multiple active iron-transport processes both in wild type microbes and in selected mutants that are deficient in some outer membrane iron-transport receptors.Conclusions: The concept of active iron-transport-mediated drug delivery can now be extended to drug conjugates that can enter the cell through multiple outer membrane receptors. Mutants that are resistant to such conjugates should be severely impaired in iron uptake, and therefore particularly prone to iron starvation.     

Oral colon-targeted mucoadhesive micelles with enzyme-responsive controlled release of curcumin for ulcerative colitis therapy

Although multitudinous nanoscale drug-delivery systems (DDSs) have been recommended to improve anti-ulcerative colitis (UC) outcomes, to enhance the mucoadhesion of nanosystems on the colon and specifically release the loaded drugs in response to the colon micro-environment would be critical factors. The application of curcumin (Cur), an acknowledged anti-UC phytochemical compound, for UC therapy requires more efficient nano-carriers to improve its therapeutic outcome. Herein, we developed the colon-targeted nano-micelles with mucoadhesive effect and Azo reductase-triggered drug release profiles for Cur delivery in UC treatment. Specifically, the amphiphilic block polymer containing the Azo-reductase sensitive linkage (PEG-Azo-PLGA), and catechol-modified TPGS (Cat-TPGS) were synthesized respectively. Based on the self-assembly of the mixed polymers, Cur-micelles (142.7 ± 1.7 nm of average size, 72.36% ± 1.54% of DEE) were obtained. Interestingly, the Cur-micelles exhibited the Azo-reductase sensitive particle dissociation and drug release, the enhanced cellular uptake and the prolonged retention on colonic mucosa, mediated by the strong mucoadhesion of catechol structure. Ultimately, Cur-micelles significantly mitigated colitis symptoms and accelerated colitis repair in DSS-treated mice by regulating the intestinal flora and the levels of pro-inflammatory factors (MPO, IL-6, IL-1β, and TNF-α) related to TLR4/MyD88/NF-κB signaling pathway. This work provides an effective drug delivery strategy for anti-UC drugs by oral administration.     

Biocompatible APTES–PEG Modified Magnetite Nanoparticles: Effective Carriers of Antineoplastic Agents to Ovarian Cancer

Magnetite nanoparticles are particularly attractive for drug delivery applications because of their size-dependent superparamagnetism, low toxicity, and biocompatibility with cells and tissues. Surface modification of iron oxide nanoparticles with biocompatible polymers is potentially beneficial to prepare biodegradable nanocomposite-based drug delivery agents for in vivo and in vitro applications. In the present study, the bare (10 nm) and polyethylene glycol (PEG)–(3-aminopropyl)triethoxysilane (APTES) (PA) modified (17 nm) superparamagnetic iron oxide nanoparticles (SPIO NPs) were synthesized by coprecipitation method. The anticancer drugs, doxorubicin (DOX) and paclitaxel (PTX), were separately encapsulated into the synthesized polymeric nanocomposites for localized targeting of human ovarian cancer in vitro. Surface morphology analysis by scanning electron microscopy showed a slight increase in particle size (27?±?0.7 and 30?±?0.45 nm) with drug loading capacities of 70 and 61.5 % and release capabilities of 90 and 93 % for the DOX- and PTX-AP-SPIO NPs, respectively (p?<?0.001). Ten milligrams/milliliter DOX- and PTX-loaded AP-SPIO NPs caused a significant amount of cytotoxicity and downregulation of antiapoptotic proteins, as compared with same amounts of free drugs (p?<?0.001). In vivo antiproliferative effect of present formulation on immunodeficient female Balb/c mice showed ovarian tumor shrinkage from 2,920 to 143 mm³ after 40 days. The present formulation of APTES–PEG-SPIO-based nanocomposite system of targeted drug delivery proved to be effective enough in order to treat deadly solid tumor of ovarian cancer in vitro and in vivo.