Novel functional hyperbranched polyether polyols as prospective drug delivery systems

Multifunctional hyperbranched polyether polyols bearing protective poly(ethylene glycol) (PEG) chains with or without the folate targeting ligand at their end have been prepared. Solubilization in these polymers of a fluorescent probe, pyrene, and an anticancer drug, tamoxifen, was physicochemically investigated. It was found that PEG chains attached at the surface of these hyperbranched polymers, in addition to their well-established protective role, enhance the encapsulation efficiency of the polymers. The release of pyrene and tamoxifen observed upon addition of sodium chloride is, in most of the cases, significant only at concentrations exceeding the physiological extracellular concentration. Thus, a significant amount of the probe or drug remains solubilized inside the carriers, which is an encouraging result if the polymers are to be used for drug delivery.     

A novel micellar PEGylated hyperbranched polyester as a prospective drug delivery system for paclitaxel

A hyperbranched aliphatic polyester has been functionalized with PEG chains to afford a novel water-soluble BH40-PEG polymer which exhibits unimolecular micellar properties, and is therefore appropriate for application as a drug-delivery system. The solubility of the anticancer drug paclitaxel was enhanced by a factor of 35, 110, 230, and 355 in aqueous solutions of BH40-PEG of 10, 30, 60, and 90 mg x mL(-1), respectively. More than 50% of the drug is released at a steady rate and release is almost complete within 10 h. The toxicity of BH40-PEG was assessed in vitro with A549 human lung carcinoma cells and found to be nontoxic for 3 h incubation up to a 1.75 mg x mL(-1) concentration while LD50 was 3.5 mg x mL(-1). Finally, it was efficiently internalized in cells, primarily in the absence of foetal bovine serum, while confocal microscopy revealed the preferential localization of the compound in cell nuclei. [Figure: see text].     

Doubly hydrophilic multiarm hyperbranched polymers with acylhydrazone linkages as acid-sensitive drug carriers

A novel type of drug carrier capable of controlled drug release is proposed. It consists of an acid-sensitive doubly hydrophilic multiarm hyperbranched copolymer with a hyperbranched polyamidoamine core and many linear poly(ethylene glycol) arms. Using pH-sensitive acylhydrazone linkages, the polymer forms unimolecular micelles that can encapsulate hydrophobic drugs. Due to their amphiphilicity, the drug-loaded unimolecular micelles can self-assemble into multimolecular micelles that show acid-triggered intracellular delivery of the hydrophobic drugs.     

Generic, anthracene-based hydrogel crosslinkers for photo-controllable drug delivery

Light‐responsive polymers with controllable, reversible crosslink mechanisms have the potential to create unique biomaterials with stimulus‐controlled swelling, degradation and diffusion properties useful in tissue engineering and drug delivery applications. Generic photodimerizing polyethylene glycol–anthracene macromolecules that may be grafted to various polymers to effectively control their crosslinking via a photodimerization mechanism have been developed. These generic crosslinkers were shown to effectively introduce photoresponsive properties into hyaluronate and alginate as model hydrophilic polymers. In vitro testing using human corneal epithelial cells was used to demonstrate cytocompatibility of the resulting photogels. The effective crosslinking density of the photogels could be increased resulting in a decrease in the release rate of small and large molecules from the photogels following exposure to 365 nm light. This tuneable crosslinking has the potential to manipulate the delivery rates of therapeutics resulting in control over treatment profiles and may lend itself to various applications, which may benefit from light induced changes in crosslinking.

     

Supramolecular self-assembly and controllable drug release of thermosensitive hyperbranched multiarm copolymers

A novel temperature-responsive hyperbranched multiarm copolymer with a hydrophobic hyperbranched poly(3-ethyl-3-(hydroxymethyl)oxetane)(HBPO) core and thermosensitive poly(N-isopropylacrylamide)(PNIPAM) arms was synthesized via the atom transfer radical polymerization(ATRP) of NIPAM monomers from a hyperbranched HBPO macroinitiator.It was found that HBPO-star-PNIPAM self-assembled into multimolecular micelles(around 60 nm) in water at room temperature according to pyrene probe fluorescence spectrometry,1H N...     

Facile construction of multivalent targeted drug delivery system from Boltorn® series hyperbranched aliphatic polyester and folic acid

The conjugation of PAMAM dendrimer and folic acid is a well‐studied multivalent targeted drug delivery system, but it is expensive and difficult to be synthesized. To construct an inexpensive and well‐defined multivalent targeted drug delivery system, a cheap carrier — Boltorn® series hyperbranched aliphatic polyester — was proposed as the nanodevice to carry fluorescein, folic acid, and methotrexate. The construction follows a facile route: (1) synthesizing the carrier — a hybrid hyperbranched polymer with acyclic hydroxyls and cyclic carbonate, (2) linking fluorescein to the hyperbranched polymer via the acyclic hydroxyls, (3) opening the ring of the cyclic carbonate with the amino group of folic acid, and (4) attaching the drug methotrexate to the resulting hydroxyls by ring‐opening reaction. In this route, the peripheral hydroxyls of the hyperbranched polymer are divided into two groups and reacted with three reagents in sequence to form the desired multivalent targeted drug delivery system. Copyright © 2009 John Wiley & Sons, Ltd.     

双亲水性超支化接枝共聚物的pH响应性药物释放

首先利用阳离子开环聚合合成了超支化聚缩水甘油醚（HPG）,然后通过酯化反应制备了低接枝率的大分子引发剂HPG-Br,并进一步引发甲基丙烯酸-2-（N,N-二甲氨基）乙酯（DMAEMA）单体的原子转移自由基聚合,合成了低接枝率的双亲水性超支化接枝共聚物HPG-g-PDMAEMA,用1HNMR和GPC对聚合物结构进行了表征.并采用芘荧光探针法,HNMR和DLS研究了HPG-g-PDMAEMA在不同pH水溶液中的组装行为.以1香豆素102为模型药物研究了HPG-g-PDMAEMA聚合物在不同pH条件下的药物释放行为,发现在pH连续振荡刺激下HPG-g-PDMAEMA聚合物胶束对药物分子能实现部分＂可逆＂的释放和再包载.     

Drug release property of a pH-responsive double-hydrophilic hyperbranched graft copolymer

In this paper, we report the synthesis and self-assembly of double-hydrophilic hyperbranched graft copolymers of HPG-g-PDMAEMA, which consist of a hyperbranched polyglycerol (HPG) core and several grafted poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) arms. HPG was synthesized by cationic polymerization. Then HPG-Br macroinitiator was obtained by esterification of HPG with 2-bromoisobutyryl bromide, which was subsequently used in the preparation of HPG-g-PDMAEMA graft copolymers through atom transfer r...     

Designing responsive microgels for drug delivery applications

Microgels based on thermally responsive polymers have been widely investigated in the context of controlled release applications, with increasing recent interest on developing a clearer understanding of what physical, chemical, and biological parameters must be considered to rationally design a microgel to deliver a specific drug at a specific rate in a specific physiological context. In this contribution, we outline these key design parameters associated with engineering responsive microgels for drug delivery and discuss several recent examples of how these principles have been applied to the synthesis of microgels or microgel-based composites. Overall, we suggest that in vivo assessment of these materials is essential to bridge the existing gap between the fascinating properties observed in the lab and the practical use of microgels in the clinic. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3027–3043     

Hyperbranched copolymer micelles as delivery vehicles of doxorubicin in breast cancer cells

Four types of drug nanoparticles (NPs) based on amphiphilic hyperbranched block copolymers were developed for the delivery of the chemotherapeutic doxorubicin (DOX) to breast cancer cells. These carriers have their hydrophobic interior layer composed of the hyperbranched aliphatic polyester, Boltorn^® H30 or Boltorn^® H40, that are polymers of poly 2,2‐bis (methylol) propionic acid (bis‐MPA), while the outer hydrophilic shell was composed of about 5 poly(ethylene glycol) (PEG) segments of 5 or 10 kDa molecular weight. A chemotherapeutic drug DOX, was further encapsulated in the interior of these polymer micelles and was shown to exhibit a controlled release profile. Dynamic light scattering and transmission electron microscopy analysis confirmed that the NPs were uniformly sized with a mean hydrodynamic diameter around 110 nm. DOX‐loaded H30‐PEG10k NPs exhibited controlled release over longer periods of time and greater cytotoxicity compared with the other materials developed against our tested breast cancer cell lines. Additionally, flow cytometry and confocal scanning laser microscopy studies indicated that the cancer cells could internalize the DOX‐loaded H30‐PEG10k NPs, which contributed to the sustained drug release, and induced more apoptosis than free DOX did. These findings indicate that the H30‐PEG10k NPs may offer a very promising approach for delivering drugs to cancer cells. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

PLA nano- and microparticles for drug delivery: an overview of the methods of preparation

The controlled release of medicaments remains the most convenient way of drug delivery. Therefore, a wide variety of reports can be found in the open literature dealing with drug delivery systems. In particular, the use of nano- and microparticles devices has received special attention during the past two decades. PLA and its copolymers with GA and/or PEG appear as the preferred substrates to fabricate these devices. The methods of fabrication of these particles will be reviewed in this article, describing in detail the experimental variables associated with each one with regard to the influence of them on the performance of the particles as drug carriers. An analysis of the relationship between the method of preparation and the kind of drug to encapsulate is also included. Furthermore, certain issues involved in the addition of other monomeric substrates than lactic acid to the particles formulation as well as novel devices, other than nano- and microparticles, will be discussed in the present work considering the published literature available.     

Hybrid alginate beads with thermal‐responsive gates for smart drug delivery

Polysaccharide‐based thermo‐responsive material was prepared by grafting PNIPAAm onto hybrid alginate beads, in which a biomineralized polyelectrolyte layer was constructed aiming to enhance the mechanical strength and ensure higher graft efficiency. XPS results demonstrated that the incorporation of PNIPAAm to the hybrid beads was successful, and the PNIPAAm‐grafted beads were more hydrophilic than the ungrafted ones as indicated by their swelling behavior. The drug release behaviors revealed that the grafted beads were both thermo‐ and pH‐sensitive, and the PNIPAAm existed in the pores of the alginate beads acted as the “on–off” gates: the pores of the beads were covered by the stretched PNIPAAm to delay the drug release at 25°C and opened to accelerate the drug release at 37°C because of the shrinking of PNIPAAm molecules. This paper would be a useful example of grafting thermo‐responsive polymers onto biodegradable natural polymer substrate. The obtained beads provide a new mode of behavior for thermo‐responsive “smart” polysaccharide materials, which is highly attractive for targeting drug delivery system and chemical separation. Copyright © 2010 John Wiley & Sons, Ltd.     

Reducible polyethylenimine hydrogels with disulfide crosslinkers prepared by michael addition chemistry as drug delivery carriers: Synthesis,properties, and in vitro release

Degradable hydrogels crosslinked with disulfide bonds were prepared by Michael addition between amine groups of branched polyethylenimine and carbon–carbon double bonds of N,N′‐bis(acryloyl)cystamine. The influences of the chemical composition of the resulted hydrogels on their properties were examined in terms of morphology, surface area, swelling kinetics, and degradation. The hydrogels were uniformly crosslinked and degraded into water‐soluble polymers in the presence of the reducing agent of dithiothreitol, which improved the control over the release of encapsulated drug. The degradation of hydrogels can trigger the release of encapsulated molecules, as well as facilitate the removal of empty vehicles. Results obtained from in vitro drug release suggested that the disulfide crosslinked hydrogels exhibited an accelerated release of encapsulated drug in dithiothreitol‐containing PBS buffer solution. Moreover, the drug release rate decreased gradually with increasing crosslinking density. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 4074–4082, 2009     

Synthesis and characterization of a starch‐modified hydrogel as potential carrier for drug delivery system

Synthesis and characterization of a new hydrogel were carried out using a chemically modified starch (starch‐M) consisting of coupling C?C bounds coming from glycidil methacrylate (GMA) onto the polysaccharide structure. ¹³C NMR, ¹H NMR, and FT‐IR spectroscopies were used to confirm the incorporation of such groups onto the starch‐M. The hydrogel was prepared by a crosslinking polymerization of starch‐M using sodium persulfate as an initiating agent. The starch‐M hydrogel shows morphology clearly different from that of the raw starch film due to the presence of voids on its surface. The swelling process of the starch‐M hydrogel was not significantly affected by changes on the temperature or on pH of the surrounding liquid, indicating the such behavior can be then understood by a diffusional process, resulting from its physical–chemical interactions with the solvent. The values of the diffusional exponent n were on the order of 0.45–0.49 for the range of pHs investigated, demonstrating that the water transport mechanism of starch‐M hydrogel is more dependent on Fickian diffusion, that is, controlled by water diffusion. Such starch‐M hydrogel is a promising candidate to be used in transporting and in preserving acid‐responsive drugs, such as corticoids, for the treatment of colon‐specific diseases, for example, Crohn's disease. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2567–2574, 2008     

Optimization of bioreducible micelles self‐assembled from amphiphilic hyperbranched block copolymers for drug delivery

Dendritic polymers‐based unimolecular micelles with enhanced stability are attractive carriers. However, the preparation of dendrimers or dendrons with higher generation remains substantially synthetic challenge due to the increased steric hindrance, multistep and tedious preparation, and low yields. The adoption of Boltorn H40, a commercially available dendritic polymer of Boltorn family containing multiple hydroxyl groups with various functionalities as a dendrimer‐based starting core template for the generation of hyperbranched polymers, offers a straightforward solution to address this problem. To develop universal strategies toward H40‐based amphiphilic block copolymers, the “grafting from” and “grafting to” approaches were both applied in this study. The reduction‐insensitive block copolymers, H40‐b‐poly(ɛ‐caprolactone)‐b‐poly(oligo(ethylene glycol) monomethyl ether methacrylate) (H40‐b‐PCL‐b‐POEGMA), were synthesized by “grafting from” including sequential ring‐opening polymerization (ROP) and atom transfer radical polymerization (ATRP). The core structure and the polymer composition of the nonreducible amphiphilic hyperbranched block copolymers were optimized toward better properties and performance for drug delivery applications, and H40‐PCL₁₅‐b‐POEGMA₂₃ was screened as the best polymer construct relative to H20‐PCL₁₅‐b‐POEGMA₂₃ and H40‐PCL₁₅‐b‐POEGMA₃₂ in terms of micelle stability and drug loading capacity. Therefore, the reducible H40‐b‐PCL‐SS‐POEGMA with an identical core and polymer composition to that of H40‐PCL₁₅‐b‐POEGMA₂₃ was further prepared by “grafting to” using click coupling between H40‐PCL‐azide and P(OEGMA)‐alkyne. The delivery efficacy evaluated by an in vitro cytotoxicity study revealed that the resulting DOX‐loaded reducible micelles of H40‐PCL₁₅‐SS‐POEGMA₂₃ produced greater cytotoxicity in cancer cells than in normal cells and macrophages, therefore, are promising carriers for anticancer drug delivery. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 1383–1394     

UV-photocrosslinking of inulin derivatives to produce hydrogels for drug delivery application

In this work, INU, a natural polysaccharide, has been chemically modified in order to obtain new photocrosslinkable derivatives. To reach this goal, INU has been derivatized with MA thus obtaining four samples (INU-MA derivatives) as a function of the temperature and time of reaction. An aqueous solution of the derivative INU-MA1 was irradiated by using a UV lamp with an emission range from 250 to 364 nm and without using photoinitiators. The obtained hydrogel showed a remarkable water affinity but it underwent a partial degradation in simulated gastric fluid. To overcome this drawback, INU-MA1 was derivatized with SA thus obtaining the INU-MA1-SA derivative designed to produce a hydrogel showing a low swelling and an increased chemical stability in acidic medium. Ibuprofen, as a model drug, was loaded by soaking into INU-MA1 and INU-MA1-SA hydrogels and its release from these matrices was evaluated in simulated gastrointestinal fluids. INU-MA1 hydrogel showed the ability to quickly release the entrapped drug thus indicating its potential as a matrix for an oral formulation. INU-MA1-SA hydrogel showed a pH-responsive drug delivery. Therefore it is a promising candidate for controlled drug release in the intestinal tract.     

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     

Smart polymer grafted silica based drug delivery systems

Smart polymers are a special class of polymers, which respond to the various external stimuli by changing their properties. Recent developments in synthetic polymer chemistry have provided the possibility of designing and synthesis of various new stimuli-responsive polymers. These stimuli-responsive polymers can be used to prepare smart drug delivery systems (DDS) by grafting them on various nanomaterials. The main aim of this review is to present collective information on various stimuli-responsive polymers grafted on silica nanoparticles for the preparation of smart DDS. The stimuli covered are pH, temperature, redox, reactive oxygen species (ROS), glucose concentration, enzymes, magnetic field, and so forth. The structures of various stimuli-responsive polymers are shown with their relevance to the preparation of smart DDS. The crucial roles of macromolecular design and synthesis of smart polymers in the development of stimuli-responsive DDS are discussed with examples from literature and the challenges that still exist in this area of research are presented.