Biodegradable depsipeptide–PDO–PEG-based block copolymer micelles as nanocarriers for controlled release of doxorubicin

Nowadays, biodegradable amphiphilic block copolymers with stable performance and adjustable structure have attracted the interests of researchers in the field of drug delivery. In this work, the triblock copolymer, P(SBMD-co-PDO)-b-PEG-b-P(SBMD-co-PDO), was successfully synthesized by ring-opening polymerization of 3(S)-sec-butyl-morpholine-2,5-dione (SBMD) and p-dioxanone (PDO) with poly(ethylene glycol) (PEG) as the initiator. In phosphate buffered solution (PBS), these copolymers could self-assemble into nano-sized micelles that have a hydrophobic P(SBMD-co-PDO) core surrounded by a hydrophilic PEG shell. Because of the strong hydrogen bonding and hydrophobic interactions, doxorubicin (DOX) was loaded into the micelles with high loading capacity (LC, up to 28.4%) and encapsulation efficiency (EE, up to 62.5%). The drug-loaded micelles showed sustained-release of DOX along with the hydrolytic degradation of the micelles in PBS. Therefore, these amphiphilic triblock copolymers have potential as drug matrix for controlled release.     

Prospects for polymer therapeutics in Parkinson's disease and other neurodegenerative disorders

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons and represents a growing health burden to western societies. Like many neurodegenerative disorders the cause is unknown, however, as the pathogenesis becomes ever more elucidated, it is becoming clear that effective delivery is a key issue for new therapeutics. The versatility of today's polymerization techniques allows the synthesis of a wide range of polymer materials which hold great potential to aid in the delivery of small molecules, proteins, genetic material or cells. In this review, we capture the recent advances in polymer based therapeutics of the central nervous system (CNS). We place the advances in historical context and, furthermore, provide future prospects in line with newly discovered advancements in the understanding of PD and other neurodegenerative disorders. This review provides researchers in the field of polymer chemistry and materials science an up-to-date understanding of the requirements placed upon materials designed for use in the CNS aiding the focus of polymer therapeutic design.     

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.     

Folate-encoded and Fe3O4-loaded polymeric micelles for dual targeting of cancer cells

Diblock copolymers of poly(ethylene glycol) (PEG) and poly(?-caprolactone) (PCL) bearing a tumor-targeting ligand, folate, were self-assembled into micelles. Superparamagnetic iron oxide (SPIO) nanoparticles and an anticancer drug doxorubicin (DOX) were coencapsulated within the micelles less than 100 nm in diameters. These SPIO-DOX-loaded micelles were superparamagnetic at room temperature, but turned ferrimagnetic at 10 K, consistent with magnetic properties of primary SPIO nanoparticles. Cell culture experiments demonstrated the potential of these polymeric micelles as an effective dual targeting nanoplatform for the delivery of anticancer drugs. Folate attachment to micelles resulted in the recognition of the micelles by tumor cells over-expressing folate receptors, leading to facilitation in cellular uptake of micelles, and the transport efficiency of the SPIO-loaded and folate-functionalized micelles into the tumor cells can be further enhanced by applying an external magnetic field to the cells.     

Preparation of polymer nanoparticles loaded with doxorubicin for controlled drug delivery

The preparation of polymer nanoparticles loaded with an active principle, commonly used in cancer treatment, is investigated here from the experimental point of view. The main novelty of this work stands in the use of continuous confined impinging jets mixers in combination with realistic materials, notably the biodegradable and biocompatible copolymer poly(methoxypolyethyleneglycolcyanoacrylate-co-hexadecylcyanoacrylate) together with two forms of the drug doxorubicin. To our knowledge this is the first attempt to use for such a system a device that can be operated continuously and can be easily scaled up. Nanoparticles are produced via solvent-displacement experimenting different solvents; the effect of the other operating parameters is also investigated. Nanoparticles are characterized in terms of their size distribution and surface properties; for a limited number of samples prepared with the optimized preparation protocol further characterization (in terms of drug loading, incorporation and release profiles) is also carried out. Collected results show that the overall approach is capable of producing nanoparticles with controlled particle size distribution, drug loading and good reproducibility and that on the contrary of what reported in the literature the presence of the active principle does play an important role.     

Preparation and Characterization of Stimuli-Responsive Magnetic Nanoparticles

In this work, the main attention was focused on the synthesis of stimuli-responsive magnetic nanoparticles (SR-MNPs) and the influence of glutathione concentration on its cleavage efficiency. Magnetic nanoparticles (MNPs) were first modified with activated pyridyldithio. Then, MNPs modified with activated pyridyldithio (MNPs-PDT) were conjugated with 2, 4-diamino-6-mercaptopyrimidine (DMP) to form SR-MNPs via stimuli-responsive disulfide linkage. Fourier transform infrared spectra (FTIR), transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS) were used to characterize MNPs-PDT. The disulfide linkage can be cleaved by reduced glutathione (GHS). The concentration of glutathione plays an important role in controlling the cleaved efficiency. The optimum concentration of GHS to release DMP is in the millimolar range. These results had provided an important insight into the design of new MNPs for biomedicine applications, such as drug delivery and bio-separation.     

Single-step assembly of polymer-lipid hybrid nanoparticles for mitomycin C delivery

Mitomycin C is one of the most effective chemotherapeutic agents for a wide spectrum of cancers, but its clinical use is still hindered by the mitomycin C (MMC) delivery systems. In this study, the MMC-loaded polymer-lipid hybrid nanoparticles (NPs) were prepared by a single-step assembly (ACS Nano 2012, 6:4955 to 4965) of MMC-soybean phosphatidyhlcholine (SPC) complex (Mol. Pharmaceutics 2013, 10:90 to 101) and biodegradable polylactic acid (PLA) polymers for intravenous MMC delivery. The advantage of the MMC-SPC complex on the polymer-lipid hybrid NPs was that MMC-SPC was used as a structural element to offer the integrity of the hybrid NPs, served as a drug preparation to increase the effectiveness and safety and control the release of MMC, and acted as an emulsifier to facilitate and stabilize the formation. Compared to the PLA NPs/MMC, the PLA NPs/MMC-SPC showed a significant accumulation of MMC in the nuclei as the action site of MMC. The PLA NPs/MMC-SPC also exhibited a significantly higher anticancer effect compared to the PLA NPs/MMC or free MMC injection in vitro and in vivo. These results suggested that the MMC-loaded polymer-lipid hybrid NPs might be useful and efficient drug delivery systems for widening the therapeutic window of MMC and bringing the clinical use of MMC one step closer to reality.     

Review of crosslinked and non‐crosslinked copolyesters for tissue engineering and drug delivery

Novel degradable biomedical materials are found to have huge potential applications in fields such as drug delivery and release, orthopedic fixation support and tissue engineering. Utilization of polymers as biomaterials has greatly impacted the advancement of modern medicine. In this review, some new degradable biomedical copolyesters reported in recent years are introduced and discussed in combination with some of our research results, including non‐crosslinked copolyesters, crosslinked copolyesters and their corresponding derivatives. The molecular design, chemical structures and related properties of these biodegradable copolyesters are reported. In summarizing the review, the development, potential applications and future directions of degradable biomedical copolyesters are discussed. © 2013 Society of Chemical Industry     

Morphology modulation of polymeric assemblies by guest drug molecules: TEM study and compatibility evaluation

Amphiphilic copolymers with poly(N-isopropylacrylamide) and ethyl tryptophan, ethyl 4-aminobenzoate, or ethyl glycinate as side groups were synthesized. Assemblies based on these copolymers were employed as model systems to investigate the morphology transformation upon loading of various hydrophobic drugs. TEM observation suggested that the loading of non-steroidal anti-inflammatory drugs, including ibuprofen, ketoprofen, indomethacin, naproxen and mefenamic acid, can trigger a significant morphological transformation of assemblies based on copolymers with low substitution of hydrophobic group. On the other hand, the introduction of steroidal anti-inflammatory drugs (medroxyprogesterone acetate, prednisone acetate and dexamethasone) and aliphatic acids (caprylic acid, tetradecanoic acid and stearic acid) has no significant effect on the morphology of assemblies derived from the same copolymers, although they do have some effect on the morphology of assemblies based on copolymers with high content of hydrophobic group. In addition, the morphology of assemblies is well correlated with drug loading efficiency. An occurrence of morphology transformation means a higher drug loading, and vice versa. Various physicochemical parameters including partition coefficient, molecular volume and solubility parameters were calculated according to group contribution method. Analysis of these data pointed to the fact that a combination of molecular volume and solubility parameters can be used as a measure to judge whether one molecule is ‘active’ or ‘neutral’. This rule can also be applied to evaluate the compatibility between candidate drugs and nanocarriers based on these copolymers.     

The use of polymer-based nanoparticles and nanostructured materials in treatment and diagnosis of cardiovascular diseases: Recent advances and emerging designs

This review summarizes important advances in polymer-based nanotechnologies for the treatment and diagnosis of cardiovascular diseases, focusing on nanoparticles and nanostructured materials/devices. The current state of the art and design parameters are discussed with the aim of providing a source of information that can aid in the development of new treatments by bridging between materials development, preclinical, and clinical trials. This is highly relevant as cardiovascular diseases remain a leading cause of death worldwide and as current treatments burden the healthcare systems with great costs. Different strategies, from targeting theranostic nanocarriers, to dual-drug depot systems, injectable cell scaffolds, and LDL acceptors are treated. The review ends with a concluding outlook on the possibilities and challenges presented to polymer-based nanotechnologies in cardiovascular disease therapy.     

Biodegradable macromolecular conjugates of citropin: Synthesis,characterization and in vitro efficiency study

The effective synthesis of citropin–polymer conjugates was described in this paper. The obtained biodegradable polymeric matrices and polymeric conjugates were characterized using ¹H or ¹³C NMR and Fourier transform infrared spectroscopies, gel permeation chromatography and scanning electron microscopy. Toxicity of polymers was evaluated with bacterial luminescence test and two protozoan assays. The in vitro release study of citropin from the obtained conjugates was investigated. The preliminary results of antimicrobial activity of the obtained macromolecular conjugates against Bacillus anthracis, Enterococcus hirae and Staphylococcus aureus were also discussed. The peptide had a high level of antimicrobial activity during 3–5 weeks of the degradation process. The development of biodegradable citropin systems should be of a great interest in the delivery systems of antimicrobial agents.     

Paclitaxel-loaded nanoparticles of star-shaped cholic acid-core PLA-TPGS copolymer for breast cancer treatment

A system of novel nanoparticles of star-shaped cholic acid-core polylactide-d-α-tocopheryl polyethylene glycol 1000 succinate (CA-PLA-TPGS) block copolymer was developed for paclitaxel delivery for breast cancer treatment, which demonstrated superior in vitro and in vivo performance in comparison with paclitaxel-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles and linear PLA-TPGS nanoparticles. The paclitaxel- or couramin 6-loaded nanoparticles were fabricated by a modified nanoprecipitation method and then characterized in terms of size, surface charge, surface morphology, drug encapsulation efficiency, and in vitro drug release. The CA-PLA-TPGS nanoparticles were found to be spherical in shape with an average size of around 120 nm. The nanoparticles were found to be stable, showing no change in the particle size and surface charge during 90-day storage of the aqueous solution. The release profiles of the paclitaxel-loaded nanoparticles exhibited typically biphasic release patterns. The results also showed that the CA-PLA-TPGS nanoparticles have higher antitumor efficacy than the PLA-TPGS nanoparticles and PLGA nanoparticles in vitro and in vivo. In conclusion, such nanoparticles of star-shaped cholic acid-core PLA-TPGS block copolymer could be considered as a potentially promising and effective strategy for breast cancer treatment.     

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.     

Doxorubicin-loaded cholic acid-polyethyleneimine micelles for targeted delivery of antitumor drugs: synthesis,characterization, and evaluation of their in vitro cytotoxicity

Doxorubicin-loaded micelles were prepared from a copolymer comprising cholic acid (CA) and polyethyleneimine (PEI) for the delivery of antitumor drugs. The CA-PEI copolymer was synthesized via pairing mediated by N,N’-dicyclohexylcarbodiimide and N-hydroxysuccinimide using dichloromethane as a solvent. Fourier transform infrared and nuclear magnetic resonance analyses were performed to verify the formation of an amide linkage between CA and PEI and doxorubicin localization into the copolymer. Dynamic light scattering and transmission electron microscopy studies revealed that the copolymer could self-assemble into micelles with a spherical morphology and an average diameter of <200 nm. The CA-PEI copolymer was also characterized by X-ray diffraction and differential scanning calorimetry. Doxorubicin-loaded micelles were prepared by dialysis method. A drug release study showed reduced drug release with escalating drug content. In a cytotoxicity assay using human colorectal adenocarcinoma (DLD-1) cells, the doxorubicin-loaded CA-PEI micelles exhibited better antitumor activity than that shown by doxorubicin. This is the first study on CA-PEI micelles as doxorubicin carriers, and this study demonstrated that they are promising candidates as carriers for sustained targeted antitumor drug delivery system.     

Chemotherapeutic engineering: Vitamin E TPGS-emulsified nanoparticles of biodegradable polymers realized sustainable paclitaxel chemotherapy for 168 h in vivo

A full spectrum of proof-of-concept research from nanoparticle preparation and characterization, in vitro drug release, cellular uptake and cytotoxicity, to in vivo pharmacokinetics and xenograft tumor model is developed in this paper to demonstrate how nanoparticles of biodegradable polymers can be applied to formulate anticancer drugs to avoid use of toxic adjuvant and to enable sustained and controlled chemotherapy. Paclitaxel-loaded poly(lactic-co-glycolic acid) nanoparticles were prepared by solvent extraction/evaporation with vitamin E TPGS as the emulsifier, which has much higher emulsification effects and better biocompatibility than other chemical emulsifiers such as polyvinyl alcohol (PVA), resulting in a high drug encapsulation efficiency, high uptake of nanoparticles by cancer cells, and sustainable pharmacokinetics. In vitro C6 cell mortality experiments demonstrated that the nanoparticle formulation was five times more effective than Taxol^®. In vivo pharmacokinetics measurements showed that the nanoparticle formulation had a comparable value of the area-under-the-curve (AUC) with that of Taxol^®, but never exceeded the maximum tolerance level, and hence should greatly reduce the side effects compared with Taxol^®. Moreover, the nanoparticle formulation realized a sustainable therapeutic time of 168 h in comparison with 22 h for Taxol^® at a same dose of 10 mg/kg and achieved four times greater drug tolerance than Taxol^®.     

化工原理课程理论教学与实践教学改革探索

从化工原理课程的教材建设、实验室建设、课程设计等方面提出改革建议，并以实例将化工原理换热器选型设计与污泥中温厌氧发酵相结合，从而加强课程设计训练。     

Dendronized polymer as building block for layer-by-layer assembly: Polyelectrolyte multilayer films for incorporation and controlled release of water-insoluble dye

The multilayer films of the carboxylic acid terminated Fréchet-type dendronized polymer (denpol) and poly(diallyl-dimethylammonium chloride) (PDDA) were fabricated using the electrostatic layer-by-layer (LbL) assembly technique on planar substrates. The influence of pH and ionic strength of the polyelectrolyte dipping solutions on the fabrication of the PDDA/denpol multilayer films has been investigated in detail. AFM images showed that pH of the polyeletrolyte dipping solutions can obviously influence the surface morphology and roughness of the denpol layer in the multilayer films. We also use a preassembly method for incorporating water-insoluble molecule of pyrene into interior of denpol, and then fabricate the PDDA/pyrene-loaded denpol multilayer films. Moreover, we demonstrated that the loaded pyrenes can be released from the LbL films, which can be controlled by ionic strength of immersing solutions. Interestingly, the pyrene-released multilayer film can be used to reload pyrene when immersing the pyrene-released film into a saturated aqueous solution of pyrene.     

Application of polymeric nanofibers in medical designs,part IV: Drug and biological materials delivery

Nanotechnology has potential applications in different sciences, especially in the biological sciences and medicine. The development of nanofibers has greatly enhanced the scope for fabricating designs that can potentially use in medical sciences. Nanofibers mimic the porous topography of natural extracellular matrix, and are advantageous for tissue regeneration and also sustained release of encapsulated drug or growth factor. In part IV the author summarizes the currently available applications of nanofibers in drug and biological materials delivery.     

Synthesis and characterization of poly(N‐vinyl‐2‐pyrrolidone) grafted sodium alginate hydrogel beads for the controlled release of indomethacin

Graft copolymers of sodium alginate (NaAlg) with N‐vinyl‐2‐pyrrolidone were prepared using azobisisobutyronitrile as initiator. The graft copolymers (NaAlg‐g‐PVP) were characterized with Fourier transform infrared spectroscopy, elemental analysis, and differential scanning calorimetry. Polymeric hydrogel beads of NaAlg and NaAlg‐g‐PVP were prepared by crosslinking method using glutaraldehyde (GA) as a crosslinker in the hydrochloric acid catalyst (HCl) and these beads were used to deliver anti‐inflammatory drug, indomethacin (IM). Chemical stability of the IM after encapsulation into beads was confirmed by FTIR. Preparation conditions of the NaAlg‐g‐PVP beads were optimized by considering the percentage entrapment efficiency, particle size, swelling capacity and their release data. In vitro release studies were performed in simulated gastric fluid (pH 1.2) for the initial 2 h, followed by simulated intestinal fluid (pH 7.4) for 4 h. Effects of GA concentration, exposure time to GA, drug/polymer (d/p) ratio, and concentration of HCl on the release of IM were discussed. It was observed that IM release from the beads decreased with increasing GA concentration and exposure time. IM release also decreases with increasing d/p ratio and HCl concentration. The highest IM release was obtained to be 77% for beads crosslinked with 0.027M GA. Swelling experiments were also performed to compute molecular mass between crosslinks of the beads. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008