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.     

Supramolecular Proteoglycan Aggregate Mimics: Cyclodextrin‐Assisted Biodegradable Polymer Assemblies for Electrostatic‐Driven Drug Delivery

Self‐assembled, noncovalent polymeric biodegradable materials mimicking proteoglycan aggregates were synthesized from inclusion complexes of cationic surfactants with γ‐cyclodextrin and the natural anionic polymer hyaluronan. The amorphous structure of this ternary system was proven by X‐ray diffraction and thermal analysis. Light‐scattering measurements showed that there was a competition between hyaluronic acid and the surfactant for the cyclodextrin cavity. These self‐assembled supramolecular matrices were loaded with both hydrophilic and lipophilic drug substances for dissolution studies. The release of the entrapped drugs was found to be controlled by cations in the surrounding media and by biodegradation. Slow drug release in an ion‐free medium became faster in physiological salt solution in which the macroscopic polymer matrix was disassembled. In contrast, the enzymatic degradation of hyaluronan was hindered in the polymeric matrix. The supramolecular systems consisting of γ‐cyclodextrin as a macrocyclic host, a cationic surfactant guest, and hyaluronic acid as the anionic polymer electrostatically cross‐linked by the inclusion complex of the first two was found to be a novel drug‐delivery system for the controlled release of traditional drugs such as curcumin and ketotifen and proteins such as bovine serum albumin.     

Physicochemical aspects of drug delivery and release from polymer-based colloids

Recent advances in the preparation/loading, surface properties, and applications of polymer-based colloidal drug delivery and release systems, such as block copolymer micelles, polymer nano- and microparticles, polymer-modified liposomes, and chemical and physical hydrogels are presented. Drug release from polymer-based systems is affected by the drug–polymer interactions as well as the polymer microstructure and dissociation/erosion properties. Surface modification with poly(ethylene oxide) has become common in improving the biocompatibility and biodistribution of drug delivery carriers. Site-specific drug delivery can be achieved by polymer-based colloidal drug carriers when ligands of targeting information are attached on the carrier surface or when a phase transition is induced by an external stimulus. While significant progress in being made, many challenges remain in preserving the biological activity and attaining the desired drug release properties, especially for protein and DNA drugs.     

Biodegradable polymeric nanoparticles based on amphiphilic principle: construction and application in drug delivery

The use of nanotechnology in drug-delivery systems (DDS) is attractive for advanced diagnosis and treatment of cancer diseases. Biodegradable polymeric nanoparticles, for example, have promising applications as advanced drug carriers in cancer treatment. In this review, we discuss the development of drug-delivery systems based on an amphiphilic principle mainly conducted by our group for anti-cancer drug delivery. We first briefly address the synthetic chemistry for amphiphilic biodegradable polymers. In the second part, we summarize progress in the application of self-assembled polymer micelles using amphiphilic biodegradable copolymers as anti-tumor drug carriers.     

Sustained release of guaifenesin and ipriflavone from biodegradable coatings

Biodegradable plastics are an interesting class of drug carriers for controlled release, as they can decompose to nontoxic, readily bioresorbable products and are advantageous over conventional biomaterials because they do not require surgical retrieval from the body after completion of treatment. In this work, films of poly(d,l-lactic acid) (d,l-PLA) were deposited by the solvent casting technique, onto the surfaces of stainless steel plates and their biodegradation was studied after immersion in buffer solutions. The release of two model drugs, i.e. guaifenesin and ipriflavone, from the above d,l-PLA systems loaded with these compounds at various concentrations, was also studied.The experimental results showed that for low drug concentrations, the release of guaifenesin is controlled by the biodegradation rate of PLA, whereas for high concentrations the burst effect becomes the dominant release mechanism. The rate of release is faster at low pH values probably due to an acceleration of PLA biodegradation, whereas there are no chemical interactions between drug and polymer, that could essentially influence the release rate of the drug or the biodegradation of the polymer. On the other hand, high guaifenesin concentrations produce increased porosity in the PLA matrix and seem to accelerate its biodegradation and further the drug release rate. Finally, the release of ipriflavone in a mixture of 2-propanol/water is clearly a two stage process and, again, the burst effect seems to control the delivery process at high drug concentration.In conclusion, the present study shows that similar results to those obtained with d,l-PLA tablets loaded with model drugs can be obtained with thin coatings of the same systems. This might be of interest for transfer of the existing knowledge to the design of biomedical implants, treated with coatings of d,l-PLA containing reactive compounds.     

Polymeric microspheres: a delivery system for osteogenic differentiation

Advanced drug delivery systems employing controlled release technology are being developed to address many of the difficulties associated with traditional methods of drug administration. Controlled release technology involves the use of devices such as polymer‐based disks, rods, pellets, or microspheres (MSs) that encapsulate drugs, genes, cytokines, and growth factors and release them in specific location within the body in a controlled fashion, for relatively long periods of time. Among these, microencapsulation is one of the core technologies used in polymer‐based drug delivery systems. In this regard, MS serves as microcarriers for sustain drug release facilitating their use for invasive or minimally invasive treatment. MS has significant potential for the application in bone repair, intra‐articular treatment of osteoarthritis, and biological bone growth. The present review compiles the recent advances in polymeric MS for application in bone and cartilage regeneration. Copyright © 2017 John Wiley & Sons, Ltd.     

Polymers for targeted and/or sustained drug delivery

Recent advances in the use of polymers for passive targeting of drugs attached or incorporated into polymeric species (enhanced permeability and retention, EPR) as well as active targeting of drugs by ligands or antibodies of receptors overexpressed on the surface of the targeted cells, is discussed in the present review. Examples of sustained, slow release of a drug incorporated into a polymeric matrix are cited. Drugs used for passive modes of targeting have been described in the context of polymer‐drug conjugates, drugs in the polymer coated liposomes, and drugs inserted into polymeric micelles. Active targeting of the drugs and their internalization by receptors, on the surface of the targeted cells, was also discussed. Release of the drugs inside cells, after are broken the environmentally sensitive links attaching them to polymeric platforms was described. Examples illustrate targeting drug by local heat generated by ultrasound, or by photodynamic treatment. Delivery modes of drugs incorporated into other nanoparticles and the concept of prodrugs have been investigated. Copyright © 2008 John Wiley & Sons, Ltd.     

Control of release kinetics of macromolecules from polymers

Internal and external means for controlling the release rates of large molecules, such as proteins, from ethylene—vinyl acetate copolymer matrices are presented. Internal approaches include alteration of the polymer—drug design, such as changing drug loading and particle size, coating the matrix, or altering matrix geometry. Kinetic and microstructural analyses are discussed. Applications of these polymeric systems, for instance, in delivery of insulin for diabetes, improved immunization procedures, and in developing bioassays for informational macromolecules are considered. In addition, a new approach for externally controlling release rates of drugs using magnetism has been developed. Until now, drug delivery systems were capable of delivering drugs at either constant or decreasing rates. We sought a system that permitted delivery of increased doses on demand, and achieved this by incorporating magnetic particles and drugs into polymeric matrices. Drug release rates can then be increased by an appropriate application of an external magnetic field. Over a five-day period, the magnetic field was applied ten times and drug release rates increased by up to 100% each time. Initial results indicate that this system does not cause tissue damage.     

Poly(alkylcyanoacrylate) colloidal particles as vehicles for antitumour drug delivery: a comparative study

Because of the fundamental importance of new therapeutic routes for cancer treatment, a number of systems based on colloidal particles as vehicles for the delivery of chemotherapeutic agents have been devised. The target is always to provide the proper dose of the antitumour agent only at the desired locus of action, thus reducing the unwanted side effects. The systems studied in this work are nanospheres of the biodegradable polymers poly(ethyl-2-cyanoacrylate), poly(butylcyanoacrylate), poly(hexylcyanoacrylate) and poly(octylcyanoacrylate), all suitable for parenteral administration, as vehicles for 5-fluorouracil, a well studied drug used for the treatment of solid tumours. Two loading methods have been analyzed: the first one is based on drug addition during the process of generation of the particles, by an anionic emulsion/polymerization procedure, and the subsequent drug trapping in the polymeric network. The second method is based on surface adsorption in already formed nanoparticles, after incubation in the drug solution. A detailed investigation of the capabilities of the polymer particles to load this drug is described. The main factors determining the drug incorporation to the polymer network were the type of monomer, the pH and the drug concentration. The release kinetics of 5-fluorouracil is found to be controlled by the pH of the release medium, the type of drug incorporation and the type of polymer.     

Antitumor Drug Delivery Modulated by A Polymeric Micelle with an Upper Critical Solution Temperature

Thermally sensitive polymeric nanocarriers were developed to optimize the release profile of encapsulated compounds to improve treatment efficiency. However, when referring to thermally sensitive polymeric nanocarriers, this usually means systems fabricated from lower critical solution temperature (LCST) polymers, which have been intensively studied. To extend the field of thermally sensitive polymeric nanocarriers, we for the first time fabricated a polymeric drug delivery system having an upper critical solution temperature (UCST) of 43 °C based on an amphiphilic polymer poly(AAm‐co‐AN)‐g‐PEG. The resulting polymeric micelles could effectively encapsulate doxorubicin and exhibited thermally sensitive drug release both in vitro and in vivo. A drastically improved anticancer efficiency (IC₅₀ decreased from 4.6 to 1.6 μg mL^?1, tumor inhibition rate increased from 55.6 % to 92.8 %) was observed. These results suggest that UCST‐based drug delivery can be an alternative to thermally sensitive LCST‐based drug delivery systems for an enhanced antitumor efficiency.     

Catechol polymers for pH-responsive, targeted drug delivery to cancer cells

A novel cell-targeting, pH-sensitive polymeric carrier was employed in this study for delivery of the anticancer drug bortezomib (BTZ) to cancer cells. Our strategy is based on facile conjugation of BTZ to catechol-containing polymeric carriers that are designed to be taken up selectively by cancer cells through cell surface receptor-mediated mechanisms. The polymer used as a building block in this study was poly(ethylene glycol), which was chosen for its ability to reduce nonspecific interactions with proteins and cells. The catechol moiety was exploited for its ability to bind and release borate-containing therapeutics such as BTZ in a pH-dependent manner. In acidic environments, such as in cancer tissue or the subcellular endosome, BTZ dissociates from the polymer-bound catechol groups to liberate the free drug, which inhibits proteasome function. A cancer-cell-targeting ligand, biotin, was presented on the polymer carriers to facilitate targeted entry of drug-loaded polymer carriers into cancer cells. Our study demonstrated that the cancer-targeting drug-polymer conjugates dramatically enhanced cellular uptake, proteasome inhibition, and cytotoxicity toward breast carcinoma cells in comparison with nontargeting drug-polymer conjugates. The pH-sensitive catechol-boronate binding mechanism provides a chemoselective approach for controlling the release of BTZ in targeted cancer cells, establishing a concept that may be applied in the future toward other boronic acid-containing therapeutics to treat a broad range of diseases.     

高分子包囊药物释放体系

用高分子作为载体的高分子微包囊和纳米级包囊药物制剂不仅能控制药物以一定的速度释放，而且可对生物体的生理指标变化作出反馈，因而可以成为靶向药物释放体系。通过用高分子包囊还可以延长蛋白质和多肽类药物的生理活性，提高药物稳定性，使之成为长效药物，并使一些难以口服的药物能够制成口服制剂。文章在介绍有关高分子药物释放体系的一些基本原理，以及与之相关的药学、药理学、物理化学和高分子材料科学方面知识的基础上，较全面地综述了高分子包囊药物的制备技术和应用。阐述了高分子包囊的粒径、表面积、孔度、药物性能和药含量，以及高分子包囊材料的性能对药物释放行为的影响。对药物传送机理亦进行了扼要的介绍。     

乳酸-磷酸酯共聚物为载体的高分子药物的合成及其控释研究

以5-氟尿嘧啶(5-FU)为药物模型,以乳酸-磷酸酯共聚物为高分子药物载体,合成了侧链带药的乳酸-磷酸酯共聚物药物。用¹HNMR、IR、UV谱对其结构进行了表征。测定高分子药物中5-FU的含量,研究了高分子药物的体外释药性能及共聚物组成对释药性能的影响。     

Use of osmotically active therapeutic agents in monolithic systems

The functionality of a new class of monolithic systems for the controlled release of drugs is discussed. The systems consist of uniformly dispersed particles of osmotically active therapeutic agents (drugs) in biocompatible polymeric matrices. The drug particles are encapsulated by polymers to form a multiplicity of microcapsules throughout the matrix. These osmotic film systems display zero-order drug delivery kinetics. The principal energy source governing the release of agents is osmotic in nature. When such a film is placed in an aqueous infinite sink, the film imbibes water into the outermost layer of the dispersion at a rate dictated by permeability of the polymer. Water transport into the film continues until volumetric rupture of the drug-containing capsules occurs, after which time saturated drug solution is pumped through channels created by the rupture. This process repeats itself in a serial fashion until the system is exhausted of agent. Due to the osmotic functionality of these systems, reduction of the thermodynamic activity of water outside the system can proportionally reduce the release of agent. In this paper the effects of varying drug particle size, osmotic pressure gradients, system area, drug type, polymer type, and temperature upon the drug release kinetics are presented. Application of this new technology has allowed the fabrication of several useful drug therapeutic systems.     

The effects of irradiation on controlled drug delivery/controlled drug release systems

The research of radiation effects on drugs over the past 60 years has mainly dealt with radiation sterilization of individual active pharmaceutical ingredients (APIs) in the form of pure substances or injectable solutions. However, the emergence of novel systems for drug administration and targeting via controlled drug delivery (CDD) and/or controlled drug release (CDR) has extended the use of irradiation with respect to pharmaceuticals: the capacity of radiation to act as an initiator of crosslinking has been used in the manufacturing and modification of a number of polymeric carriers with an added advantage of reducing the microbial load of products at the same time. The application of irradiation to these novel systems requires the understanding of radiation action not only on APIs alone but also on drug carriers and on the functioning of the integral CDD/CDR systems. In this paper, the significance of CDD/CDR systems is considered with a special emphasis on the role of irradiation for sterilization and crosslinking in the developments over the past 15 years. Radiation sterilization, crosslinking and degradation of the principal forms of drug carrier systems and the effects of irradiation on the release kinetics of APIs are discussed in light of radiation chemical principles. Regulatory aspects pertaining to radiation sterilization of drugs are also considered. Relevant results are summarized in tabular form.     

Investigation of drug release and 1H‐NMR analysis of the in situ forming systems based on poly(lactide‐co‐glycolide)

In situ forming biodegradable polymeric systems loaded with betamethasone (BTM) and betamethasone acetate (BTMA) were prepared using poly(DL ‐lactide‐co‐glycolide) (PLGA), ethyl heptanoate (EH), and N‐methyl‐2‐pyrrolidone (NMP) as the biodegradable polymer, additive, and solvent, respectively. The drug release studies were carried out in buffer (pH = 7.4, 37°C) using high performance liquid chromatography (HPLC). ¹H‐NMR was used to determine the polymer degradation behavior, release mechanism, and interactions between the polymer and drug. The ¹H‐NMR spectra showed that all interactions between the polymer and drug were hydrogen bonding. Hydroxyl groups and fluorine in drugs were involved in hydrogen bonding with PLGA polymer. In ¹H‐NMR studies, we found that the degradation rate in the systems loaded with BTMA was higher than the systems loaded with BTM because BTMA is only slightly soluble and accelerates the hydrolysis of PLGA chains. The formulations loaded with BTM had obviously lower burst release compared with BTMA loaded samples. With respect to ¹H‐NMR spectra, the mechanism of BTM release is controlled by two effective factors: solvent removal and polymer degradation. Copyright © 2008 John Wiley & Sons, Ltd.     

Redox‐ and Temperature‐Controlled Drug Release from Hollow Mesoporous Silica Nanoparticles

A controlled drug‐delivery system has been developed based on mesoporous silica nanoparticles that deliver anticancer drugs into cancer cells with minimized side effects. The copolymer of two oligo(ethylene glycol) macromonomers cross‐linked by the disulfide linker N,N′‐bis(acryloyl)cystamine is used to cap hollow mesoporous silica nanoparticles (HMSNs) to form a core/shell structure. The HMSN core is applied as a drug storage unit for its high drug loading capability, whereas the polymer shell is employed as a switch owing to its redox/temperature dual responses. The release behavior in vitro of doxorubicin demonstrated that the loaded drugs could be released rapidly at higher temperature or in the presence of glutathione (GSH). Thus, the dual‐stimulus polymer shell exhibiting a volume phase transition temperature higher than 37 °C can effectively avoid drug leakage in the bloodstream owing to the swollen state of the shell. Once internalized into cells, the carriers shed the polymer shell because of cleavage of the disulfide bonds by GSH, which results in the release of the loaded drugs in cytosol. This work may prove to be a significant development in on‐demand drug release systems for cancer therapy.     

聚合物纳米药物载体的研究进展

近年来, 大量研究结果表明纳米技术可显著提高传统药物的疾病治疗效果, 并在生物医学领域引起了广泛关注. 迄今, 多种聚合物纳米体系已被研发并用于药物的靶向递送. 随着纳米技术的不断发展, 各类生物微环境响应的功能基团也被应用于构筑新型药物载体, 以提高患病部位的药物富集及减少药物的毒副作用. 聚合物纳米药物载体在癌症治疗、 代谢类疾病治疗及抗菌等方面展现出巨大潜力. 本文系统评述了聚合物纳米药物载体的最新研究进展及在生物医药方面的应用.     

Syntheses,electrochemistry and cytotoxicity of ferrocene-containing polyaspartamides as water-soluble polymeric drug carrier/drug conjugates

A general strategy towards the syntheses of water-soluble polymeric drug carriers and their drug conjugates is described. Methods of drug uptake by cells, drug release from the polymeric carrier and the relevance of electrochemistry to drug activity of the ferrocenyl group are highlighted. The advantages of these polymeric systems are demonstrated utilising cytotoxicity results of a polyaspartamide-ferrocenyl conjugate.