Polyhydroxyalkanoates,a family of natural polymers,and their applications in drug delivery

Polyhydroxyalkanoates (PHAs) are natural biopolymers produced by various microorganisms as a reserve of carbon and energy. PHA synthesis generally occurs during fermentation under nutrient limiting conditions with excess carbon. There are two main types of PHAs, short chain length PHAs (scl‐PHAs) and medium chain length PHAs (mcl‐PHAs). The mechanical and thermal properties of PHAs depend mainly on the number of carbons in the monomer unit and its molecular weight. PHAs are promising materials for biomedical applications because they are biodegradable, non‐toxic and biocompatible. The large range of PHAs, along with their varying physical properties and high biocompatibility, make them highly attractive biomaterials for use in drug delivery. They can be used to produce tablets, micro‐ and nanoparticles as well as drug eluting scaffolds. A large range of different PHAs have been explored and the results obtained suggest that PHAs are excellent candidates for controlled and targeted drug delivery systems. © 2015 Society of Chemical Industry     

Copolymers of polyhydroxyalkanoates and polyethylene glycols: recent advancements with biological and medical significance

Copolymers of polyhydroxyalkanoates (PHAs ) and polyethylene glycols (PEGs ) have gained high significance for biological and medical applications within the past few years. PHAs are natural biopolymers (hydrophobic biopolyesters), which can be produced microbially and also synthetically, and PEGs are biocompatible hydrophilic polyethers, which are frequently used in medicine to enhance the effect of bioactive compounds. Both polymers can be conjugated with a variety of other polymers, and in particular the conjugation with each other affords hydrophobic ? hydrophilic PHA‐PEG copolymers with high significance as biomaterials. This paper describes selected recent developments in this field with a focus on synthetic approaches and the suitability of the resulting copolymers for applications in drug delivery and tissue engineering. © 2016 Society of Chemical Industry     

Poly-3-hydroxybutyrate-based constructs with novel characteristics for drug delivery and tissue engineering applications—A review

Herein, we reviewed polymeric constructs of polyhydroxyalkanoates (PHAs) at large and poly-3-hydroxybutyrate (P3HB), in particular, for drug delivery and tissue engineering applications. Polymeric constructs that can efficiently respond to numerous variations in their surroundings have gained notable attention from different industrial sectors such as biomedical, clinical, pharmaceutical, and cosmeceutical. Among them, considerable importance is given to their drug delivery and tissue engineering applications. PHAs with peculiar reference to P3HB are gaining prominence attention as candidate materials with such requisite potentialities. The unique structural and functional characteristics of PHAs and P3HB are of supreme interest and being used to engineer novel constructs for efficient drug delivery and tissue regeneration purposes. So far, an array of methodological approaches, such as in vitro, in vivo, and ex vivo techniques have been exploited though using different materials with different geometries for a said purpose. However, a low-level production majorly limits their proper exploitation. Various physiochemical characteristics and production strategies have been introduced in this review. The data have been summarized on PHAs production by several microorganisms aiming to cover the scope of the last 10 years. The present review highlights the recent applications of PHAs and P3HB-based constructs, such as micro/nanoparticles, biocomposite, nanofibers, and hydrogels as novel drug carries for regenerative medicine and tissue engineering. In summary, drug delivery and tissue engineering potentialities of PHAs and P3HB-based constructs are discussed with suitable examples and envisioned directions of future developments.     

Polyhydroxyalkanoates: Recent Advances in Their Synthesis and Applications

Polyhydroxyalkanoates (PHAs) are microbial biopolymers (polyesters) that have a wide range of functions and applications. They serve in nature mainly as carbon and energy storage materials for a variety of microorganisms. In past decades, their utilization has attracted much attention, from commodities and degradable plastics to specialty performance materials in medicine. PHA biosynthesis has been well understood, and it is now possible to design bacterial strands to produce PHAs with desired properties. The substrates for the fermentative production of PHAs are very manifold: some are derived from food‐based carbon sources (e.g., fats and oils (triglycerids)), thus raising concerns with regard to the sustainability of their productions in terms of crop area and food. In addition, hemicellulose hydrolysates, crude glycerol, and methanol are very promising carbon sources for the sustainable production of PHAs. The integration of PHA production within a modern biorefinery is an important issue and can result in a simultaneous production of biofuels and bioplastics. Furthermore, many chemical‐synthetic procedures by means of efficient catalysts can give access to a variety of PHAs. This article summarizes recent developments in these fields and emphasizes the importance of a sustainable PHA‐based industry. Practical Applications: Practical applications of the microbial polyesters PHAs are, for example, a variety of sustainably produced commodities as well as special applications in (bio)medicine, for example, tissue engineering.     

Development of tunable biodegradable polyhydroxyalkanoates microspheres for controlled delivery of tetracycline for treating periodontal disease

This article was aimed at preparation and characterization of drug delivery carriers made from biodegradable polyhydroxyalkanoates (PHAs) for slow release of tetracycline (TC) for periodontal treatment. Four PHA variants; polyhydroxybutyrate (PHB), poly(hydroxybutyrate‐co‐hydroxyvalerate) with 5, 12, and 50% hydroxyvalerate were used to formulate TC‐loaded PHA microspheres by double emulsion‐solvent evaporation method. We also compared the effect of different molecular weight (M_w) of polyvinyl alcohol (PVA) acting as surface stabilizer on particle size, drug loading, encapsulation efficiency, and drug release profile. The TC‐loaded PHA microspheres exhibited microscale and nanoscale spherical morphology under scanning electron microscopy. Among formulations, TC‐loaded PHB:low M_w PVA demonstrated the highest TC loading with slow release behavior. Our results showed that the release rate from PHA microspheres was influenced by both the type of PHA and M_w of PVA stabilizer. Lastly, TC‐loaded PHB microspheres showed efficient killing activity against periodontitis‐causing bacteria, suggesting its potential application for treating periodontal disease. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 44128.     

pH responsive polymers with amino acids in the side chains and their potential applications

Design and synthesis of pH responsive polymeric materials has become an important subject in academia as well as in industrial field in recent years due to their applications in diverse field including controlled drug delivery, biomedical applications, membrane science, sensors and actuators, oil recovery, colloid stabilization, etc. Efforts have been made to incorporate stimuli‐responsive biomolecules in synthetic polymers to develop pH responsive “smart” non‐biological hybrid macromolecules with high water solubility, enhanced biocompatibility, bio‐mimetic structure and properties. This review is focused on the recent advances in side‐chain amino acid‐based pH responsive polymers synthesis and potential application aspects of these macromolecular architectures in drug and gene delivery, and other fields. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 41084.     

A review on electrospun polymer nanostructures as advanced bioactive platforms

This review article deals with latest literature studies on the potential use of polymer ultrathin and nanosized structures obtained by electrospinning to design novel engineered materials with bioactive properties. The electrofluidodynamic process offers the option to form high‐performance bioactive systems based on polymer yarns of nanofibers or coatings of nanobeads with high surface‐to‐volume ratios. The electrospun and electrosprayed nanostructures can be further functionalized by encapsulation with bioactive fillers and substances. For both scenarios, the resultant polymer nanostructures present unique bioactive properties capable of providing a beneficial impact over human's health and with improved and advanced performance for biomedicine, pharmaceutics, nutrition, bioengineering, and healthcare applications. These novel functional materials attained by the electrospinning technology can be of interest for many bioactive applications such as functional food design, food packaging, functional coatings, controlled delivery of drug solutions and, mainly, tissue engineering. This article is purposely designed to gather, for the first time, most recent and promising multi‐ and inter‐disciplinary developments based on electrospun systems for bioactive applications, which are either bioactive material concepts or can be advantageously applied to become such. POLYM. ENG. SCI., 56:500–527, 2016. © 2016 Society of Plastics Engineers     

Surface Modification of Polyhydroxyalkanoates toward Enhancing Cell Compatibility and Antibacterial Activity

Biomaterials for in vivo application should induce positive interaction with various histocytes and inhibit bacteria inflection as well. Cells and/or bacteria response to the extracellular environment is therefore the basic principle to design the biomaterials surface in order to induce the specific biomaterial–biological interaction. Polyhydroxyalkanoate (PHAs) are of growing interests because of their natural origin, biodegradability, biocompatibility, and thermoplasticity; however, quite inert and intrinsic hydrophobic characteristics have hindered their extensive usage in medical applications. Surface modification of PHAs tailors the chemistry, wettability, and topography without altering the bulk properties, and introduces specific proteins/peptides and/or antibacterial agents to mediate cell–matrix interactions. This review describes the recent developments on the surface modification of PHAs to construct cell compatible and antibacterial surfaces.     

In vitro production of polyhydroxyalkanoates: achievements and applications

The mechanisms of polyhydroxyalkanoate (PHA) production have been studied for over half a century. However, despite numerous improvements in the control of monomer composition, genetically‐engineered host organisms, fermentation strategies and polymer recovery processes they remain uncompetitive compared with petrochemical plastics. Recently, interest has developed in the enzyme‐catalysed production of PHAs in vitro. This has allowed the study of enzyme kinetics and properties, and represents another strategy for the economic production of PHAs on the industrial scale. It also presents an opportunity to coat other materials in thin films of PHA so as to modify the surface properties. In vitro production offers advantages over in vivo methods as it enables greater control over monomer composition and molecular weight, does not require a biomass‐accumulation phase, simplifies downstream processing and can utilise a wider range of monomeric subunits. Copyright © 2009 Society of Chemical Industry     

Poly(4‐vinyl pyridine)‐grafted graphene oxide for drug delivery and antimicrobial applications

Graphene oxide (GO) was covalently functionalized with poly(4‐vinyl pyridine) (P4VP) by atom transfer radical polymerization for drug delivery and antimicrobial applications. The physiochemical properties, chemical structure, composition and morphology of the P4VP‐functionalized GO (GO‐P4VP) were studied. Simple physisorption of a cancer drug, camptothecin (CPT), via π ? π stacking and/or hydrophobic interactions on the GO‐P4VP was tested for drug loading and its release by altering the pH. The GO‐P4VP has low cytotoxicity, and the CPT‐loaded GO‐P4VP exhibited a high potency for killing cancer cells in vitro. Prominent antimicrobial properties against Escherichia coli and Staphylococcus aureus were also observed. Thus, the GO‐P4VP can be utilized as a drug delivery vector with high biocompatibility, solubility and stability in physiological solutions, a suitable payload capacity and excellent bacterial toxicity. Owing to its small size, low cost, large specific area, ready scalability and useful non‐covalent interactions, GO‐P4VP is a novel material for biomedical, industrial and environmental applications. © 2015 Society of Chemical Industry     

Novel amphiphilic poly(ester‐urethane)s based on poly[(R)‐3‐hydroxyalkanoate]: synthesis,biocompatibility and aggregation in aqueous solution

BACKGROUND: The aim of this work was to develop polyhydroxyalkanoates (PHAs) for blood contact applications, and to study their self‐assembly behavior in aqueous solution when the PHAs are incorporated with hydrophilic segments. To do this, poly(ester‐urethane) (PU) multiblock copolymers were prepared from hydroxyl‐terminated poly(ethylene glycol) (PEG) and hydroxylated poly[(R)‐3‐hydroxyalkanoate] (PHA‐diol) using 1,6‐hexamethylene diisocyanate as a coupling reagent. The PEG segment functions as a soft, hydrophilic and crystalline portion and the poly[(R)‐3‐hydroxybutyrate] segment behaves as a hard, hydrophobic and crystalline portion. In another series of PU multiblock copolymers, crystalline PEG and completely amorphous poly[((R)‐3‐hydroxybutyrate)‐co‐(4‐hydroxybutyrate)] behaved as hydrophobic and hydrophilic segments, respectively. RESULTS: The formation of a PU series of block copolymers was confirmed by NMR, gel permeation chromatography and infrared analyses. The thermal properties showed enhanced thermal stability with semi‐crystalline morphology via incorporation of PEG. Interestingly, the changes of the hydrophilic/hydrophobic ratio led to different formations in oil‐in‐water emulsion and surface patterning behavior when cast into films. Blood compatibility was also increased with increasing PEG content compared with PHA‐only polymers. CONCLUSION: For the first time, PHA‐based PU block copolymers have been investigated in terms of their blood compatibility and aggregation behavior in aqueous solution. Novel amphiphilic materials with good biocompatibility for possible blood contact applications with hydrogel properties were obtained. Copyright © 2008 Society of Chemical Industry     

Chemical characterization of medium‐chain‐length polyhydroxyalkanoates (PHAs) recovered by enzymatic treatment and ultrafiltration

BACKGROUND: Medium‐chain‐length polyhydroxyalkanoates (PHAs) are biodegradable polyesters accumulated intracellularly as energy resources by bacterial species such as Pseudomonas putida. The most popular method for PHA recovery is solvent extraction using trichloromethane (chloroform) and methyl alcohol (methanol). An alternative method is enzymatic treatment, which eliminates usage of these hazardous solvents. This research focuses on the characterization of PHAs recovered by enzymatic treatments and ultrafiltration. Comparisons are made with conventional solvent extracted PHA. RESULTS: The purity of PHA in water suspension recovered by enzymatic treatments as analyzed by gas chromatography was 92.6%. Enzymatically recovered PHA was comparable to conventional solvent‐extracted PHA, which had a purity of 95.5%. PHA was further characterized for functional group analysis, structural composition analysis and molecular weight determination. It was found that the molecular weight of the PHA recovered by enzymatic treatment was less than solvent‐extracted PHA, probably due to degradation of the lipopolysaccharide layer. However, functional group and structural composition analyses showed similar results for PHA recovered by both methods. CONCLUSION: PHAs recovered through enzymatic digestion treatment have good comparability with solvent‐extracted PHAs. Thus enzymatic digestion has great potential as an alternative recovery method. Copyright © 2007 Society of Chemical Industry     

TiO2纳米结构作为载体在药物缓控释传递系统的应用

TiO₂纳米结构以其生物相容性好、机械强度高、耐热耐腐蚀等优点,在药物缓控释传递系统载体应用方面引起广泛关注。结合近几年研究报道,本文将单一和功能化TiO₂纳米结构作为药物缓控释载体进行分类,简述了制备方法、结构表征、载药方法、释药机理等,分析了功能化TiO₂纳米结构修饰结合外界刺激响应在药物缓控释系统的应用。结果表明,相比单一结构,功能化修饰后的TiO₂纳米结构具有载药率高、缓控释效果明显、生物相容性好等优点;功能化修饰结合外界刺激响应,进一步提升药物缓控释效果;而相比单一和双重刺激响应,多重刺激响应能够更好地实现局部靶向释药。最后预测该纳米结构作为药物缓控释传递系统载体的研究发展方向并指出目前实现临床应用所面临的问题。     

Polybetaines in Biomedical Applications

Polybetaines, that have moieties bearing both cationic (quaternary ammonium group) and anionic groups (carboxylate, sulfonate, phosphate/phosphinate/phosphonate groups) situated in the same structural unit represent an important class of smart polymers with unique and specific properties, belonging to the family of zwitterionic materials. According to the anionic groups, polybetaines can be divided into three major classes: poly(carboxybetaines), poly(sulfobetaines) and poly(phosphobetaines). The structural diversity of polybetaines and their special properties such as, antifouling, antimicrobial, strong hydration properties and good biocompatibility lead to their use in nanotechnology, biological and medical fields, water remediation, hydrometallurgy and the oil industry. In this review we aimed to highlight the recent developments achieved in the field of biomedical applications of polybetaines such as: antifouling, antimicrobial and implant coatings, wound healing and drug delivery systems.     

Hollow Mesoporous Silica@Metal–Organic Framework and Applications for pH‐Responsive Drug Delivery

Metal?‐organic frameworks (MOFs), a new type of porous crystalline material, hold great potential in biomedical applications, such as drug delivery. However, the efficacy of drug delivery is limited by low drug loading. In this work, we synthesized hollow mesoporous silica (HMS)@MOF capsules that can be used as a pH‐responsive drug delivery system for the anticancer drug doxorubicin (DOX). DOX is loaded into the inner cavity of HMS. Zeolitic imidazolate framework‐8 (ZIF‐8) nanoparticles are then coated on the outer surface of the DOX‐loaded HMS. The obtained material is a capsule (denoted as DOX/HMS@ZIF), in which DOX is encapsulated. The DOX/HMS@ZIF can be used as an efficient pH‐responsive drug delivery system. DOX is not released under physiological conditions (pH 7.4), but is released at low pH (4–6) from DOX/HMS@ZIF. The DOX/HMS@ZIF capsule shows much higher cytotoxicity than free DOX and alters the delivery pathway for DOX in cancer cells, while the drug‐free HMS@ZIF shows excellent biocompatibility. This opens new opportunities to construct a safe and efficient delivery system for targeted molecules using pH‐responsive release for a wide range of applications.     

Anticancer drug delivery systems based on inorganic nanocarriers with fluorescent tracers

In recent years, anticancer nanomedicines have mainly been developed for chemotherapy and combination therapy in which the main contributing anticancer drugs are delivered by deliberately designed nano drug delivery systems (nano‐DDSs). Inorganic nanocarriers equipped with fluorescent tracers have become attractive tools to monitor the whole drug delivery and release processes. The fluorescence signal of tracers could be observed concomitantly with drug release, and thus, this strategy is of great benefit to evaluate the therapeutic effects of the nano‐DDSs. This review provides a brief overview about three inorganic nanocarriers for drug delivery, including mesoporous silica, Fe₃O₄, and hydroxyapatite. We mainly discussed about their preparation processes, drug loading capacities, and the development of different fluorescent materials (fluorescent dyes, quantum dots, fluorescent macromolecules, and rare earth metals) hybridized to nanocarriers for real‐time monitoring of drug release both in vitro and in vivo. This review also provides some recommendations for more in‐depth research in future. © 2017 American Institute of Chemical Engineers AIChE J, 64: 835–859, 2018     

Some recent advances in polyolefin functionalization

Polyolefin‐based materials are increasingly being used in many industrial applications for packaging, automotive and construction materials. The recent developments of research have been aimed at making these materials, often complex, being mixtures, block copolymers, micro‐ and nanocomposites with inorganic and organic fillers, more efficient and environmentally friendly (through recycling processes, and the use of bio‐polyolefins). In this context, functionalized polyolefins, on the one hand, play a fundamental role in improving the morphology and thus the thermal and mechanical properties of heterophase systems, and, on the other hand, provide new materials difficult to obtain by conventional synthesis in connection with the type of inserted functionality. Therefore it appears to be of interest to report and discuss here the recent results concerning the radical grafting in the melt of different functionalities onto polyolefins as well as the capability reached of modulating ad hoc the degree of grafting and the final structure/architecture of functionalized polyolefins. © 2013 Society of Chemical Industry     

Functionalized chitosan with super paramagnetic hybrid nanocarrier for targeted drug delivery of curcumin

Recently, hydrophobically functionalized polymers have been deployed as carriers to improve the encapsulation of hydrophobic drugs. The metal nanocomposites are extensively used to improve the biocompatibility of the formulation and target the drug to the specialized site. In our current study, naphthalene acetate (NAA) was incorporated into the amine group of chitosan to form a hydrophobically functionalized chitosan–NAA drug delivery carrier. The calcium ferrite nanoparticles (CFNP) were embedded in the chitosan–NAA matrix to form a super paramagnetic hybrid nanocarrier for controlled curcumin drug delivery. Various analytical techniques were performed to ensure the functional group modifications, thermal stability, surface nature and morphological behavior of synthesized hybrid carriers. The maximum encapsulation efficiency of 93.6% was obtained under the optimized conditions of drug to chitosan–NAA at 0.1, CFNP to chitosan–NAA at 0.75 and TPP to chitosan–NAA at 1.0 (w/w) ratios, respectively, by adapting Taguchi method. Drug release studies were conducted to determine the effect of pH, drug loading concentrations and magnetic field responses. The drug release data were fitted to various kinetic release models to understand the drug release mechanism. The biocompatibility of the hybrid material was tested using L929 mouse fibroblast cells. The cytotoxicity test against breast cancer cells (MCF-7) was also performed to study the anticancer property of the hybrid paramagnetic material. The prepared curcumin-loaded chitosan–NAA/CFNP was very active against cancer cells in comparison to the normal cells. The results confirmed the applicability of the hybrid nanocarriers in cancer cell-targeted drug delivery.     

Exploiting the Lactose–GM3 Interaction for Drug Delivery

Protein–protein and protein–carbohydrate interactions as a means to target the cell surface for therapeutic applications have been extensively investigated. However, carbohydrate–carbohydrate interactions (CCIs) have largely been overlooked. Here, we investigate the concept of CCI‐mediated drug delivery. Lactose‐functionalized β‐cyclodextrin (L‐β‐CD) hosting doxorubicin (Dox) was evaluated for site‐specific delivery to cancer cells via interaction with GM₃, a cell‐surface carbohydrate. The host–guest complex was evaluated in B16 melanoma cells, which express exceptionally high levels of GM₃, and acute monocytic leukemia (THP‐1) and mouse fibroblast (NIH‐3T3) cells, which lack GM₃ on the cell surface. Doxorubicin (Dox) was delivered more efficiently into B16 cells compared with NIH‐3T3 and THP‐1 cells. In B16 cells pretreated with sialidase or sodium periodate, thus preventing CCI formation, drug uptake was significantly decreased. Taken together, the results of these studies strongly support CCI‐mediated uptake via the GM₃–lactose interaction as the mechanism of controlled drug delivery.     

Quantum Dot‐Based Nanotools for Bioimaging,Diagnostics, and Drug Delivery

Quantum dots (QDs) are highly fluorescent nanocrystals with advanced photophysical and spectral properties: high brightness and stability against photobleaching accompanied by broad excitation and narrow emission spectra. Water‐soluble QDs functionalized with biomolecules, such as proteins, peptides, antibodies, and drugs, are used for biomedical applications. The advantages of QD‐based approaches to immuno‐histochemical analysis, single‐molecule tracking, and in vivo imaging (over traditional methods with organic dyes and fluorescent proteins) are explained. The unique spectral properties of QDs offer opportunities for designing systems for multiplexed analysis by multicolor imaging for the simultaneous detection of multiple targets. Conjugation of drug molecules with QDs or their incorporation into QD‐based drug‐delivery particles makes it possible to monitor real‐time drug tracking and carry out image‐guided therapy. Because of the tunability of their photophysical properties, QDs emitting in the near‐infrared have become an attractive tool for deep‐tissue mono‐ and multiphoton in vivo imaging. We review recent achievements in QD applications for bioimaging, targeting, and drug delivery, as well as challenges related to their toxicity and non‐biodegradability. Key and perspectives for further development of advanced QD‐based nanotools are addressed.