Whey protein: A functional and promising material for drug delivery systems recent developments and future prospects

Natural polymers have been extensively utilized in the past decades due to their outstanding features. Among these natural excipients, protein‐based polymers have superb features owing to their high drug binding capacity and biodegradability. Whey protein is a versatile protein‐based vehicle for drug delivery systems. It has been shown to be nontoxic, biocompatible, and biodegradable. Therefore, it has been considered as an ideal biomaterial for the design of advanced drug delivery systems. Protein‐based cargo acts as synthetic polymers counterpart for innovative delivery systems. The current review is mainly focused on application of whey proteins as an emerging carrier in drug delivery systems, achieved during the past.     

Injectable and biodegradable hydrogels: gelation, biodegradation and biomedical applications

Injectable hydrogels with biodegradability have in situ formability which in vitro/in vivo allows an effective and homogeneous encapsulation of drugs/cells, and convenient in vivo surgical operation in a minimally invasive way, causing smaller scar size and less pain for patients. Therefore, they have found a variety of biomedical applications, such as drug delivery, cell encapsulation, and tissue engineering. This critical review systematically summarizes the recent progresses on biodegradable and injectable hydrogels fabricated from natural polymers (chitosan, hyaluronic acid, alginates, gelatin, heparin, chondroitin sulfate, etc.) and biodegradable synthetic polymers (polypeptides, polyesters, polyphosphazenes, etc.). The review includes the novel naturally based hydrogels with high potential for biomedical applications developed in the past five years which integrate the excellent biocompatibility of natural polymers/synthetic polypeptides with structural controllability via chemical modification. The gelation and biodegradation which are two key factors to affect the cell fate or drug delivery are highlighted. A brief outlook on the future of injectable and biodegradable hydrogels is also presented (326 references).     

Biodegradable,implantable sustained release systems based on glutamic acid copolymers

Polymer pellets that contain drugs and may be implanted under the skin offer effective means for providing sustained, controlled drug therapy to humans and animals. Among the most useful drug delivery systems are those based on biodegradable polymers that ultimately are absorbed by the body — eliminating the need for their surgical removal. Copolymers of L-glutamic acid and γ-ethyl L-glutamate biodegrade to L-glutamic acid and ethanol, at rates that are determined by the initial copolymer composition. The materials are permeable to a wide range of drugs, including steroids, narcotic antagonists, peptide hormones, antimalarials, and anticancer agents. When fabricated into matrix rods or capsules, the copolymers have been used to release drugs in animals at constant rates for prolonged periods of time. p]In this study, rods composed of a blend of drug and copolymer were found to be useful for the long-term release (i.e., 6 to 24 months) of drugs having low aqueous solubility, such as progesterone and levonorgestrel. Capsules, composed of a copolymer sheath surrounding the drug, were better suited for shorter durations of release (i.e., up to 6 months) of drugs having higher aqueous solubility, such as luteinizing hormone-releasing hormone and naltrexone. The physical dimensions and copolymer compositions of either dosage form were readily varied to meet specific delivery rate and duration objectives while satisfying equally important degradation requirements.     

Biodegradable polymer blends and composites: An overview

Biodegradable polymers belong to a family of polymer materials that found applications ranged from medical applications including tissue engineering, wound management, drugs delivery, and orthopedic devices, to packaging and films applications. For broadening their potential applications, biodegradable polymers are modified utilizing several methods such as blending and composites forming, which lead to new materials with unique properties including high performance, low cost, and good processability. This paper reviews the recent information about the morphology of blends consisting of both biodegradable and non-biodegradable polymers and associated mechanical, rheological, and thermal properties of these systems as well as their degradation behavior. In addition, the mechanical performance of composites based on biodegradable polymers is described.     

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.     

Biomedical applications of biodegradable polymers

Utilization of polymers as biomaterials has greatly impacted the advancement of modern medicine. Specifically, polymeric biomaterials that are biodegradable provide the significant advantage of being able to be broken down and removed after they have served their function. Applications are wide ranging with degradable polymers being used clinically as surgical sutures and implants. To fit functional demand, materials with desired physical, chemical, biological, biomechanical, and degradation properties must be selected. Fortunately, a wide range of natural and synthetic degradable polymers has been investigated for biomedical applications with novel materials constantly being developed to meet new challenges. This review summarizes the most recent advances in the field over the past 4 years, specifically highlighting new and interesting discoveries in tissue engineering and drug delivery applications. © 2011 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2011     

Microencapsulation peptide and protein drugs delivery system

Many methods were used to devise peptide and protein drugs delivery system (DDS). Because of their relatively large size, they have low transdermal bioavailabilities. In systemic delivery of proteins, biodegradable material as parenteral depot formulation occupy an important place because of several aspects like protection of sensitive proteins from degradation, prolonged or modified release, pulsatile release patterns. The main objective in developing controlled release protein injectables is avoidance of regular invasive doses which in turn provide patient compliance, comfort as well as control over blood levels. This review article presents the outstanding contributions in field of microencapsulation as protein delivery systems and different approaches of protein delivery are described. Then discusses how these advances may be applied to resolve the challenges face the development of microcapsule for the controllable delivery of protein drugs.     

Development of micro- and nanosystems for drug delivery

Methods for preparing colloidal delivery systems for drugs of different chemical structures have been developed and optimized. Proteins were encapsulated in bioadhesive biodegradable starch microparticles and liposomes from negatively charged and zwitter-ionic soybean phospholipids. Proteins and a poorly watersoluble anticancer drug-tamoxifen-were encapsulated in nanoparticles based on the amphiphilic graft block copolymer dextran-poly(?-caprolactone). In vitro release studies showed sustained release of proteins and tamoxifen in different media.     

Natural and bioinspired excipients for dry powder inhalation formulations

Pulmonary drug delivery can have several advantages over other administration routes, in particular when using dry powder formulations. Such dry powder inhalation formulations generally include natural and bio-inspired excipients, which, among other purposes, are used to improve dosing reproducibility and aerosolization performance. Amino acids can enhance powder dispersibility and provide protection against moisture uptake. Sugars are used as drug-carrying diluents, stabilizers for biopharmaceuticals, and surface enrichers. Lipids and lipid-like excipients can reduce interparticle adhesive forces and are also used as constituents of liposomal drug delivery systems. Finally, biodegradable polymers are used to facilitate sustained release and targeted drug delivery. Despite their promise, pulmonary toxicity of many of the discussed excipients remains largely unknown and requires attention in future research.     

Stereocomplex Polylactide for Drug Delivery and Biomedical Applications: A Review

Polylactide (PLA) is among the most common biodegradable polymers, with applications in various fields, such as renewable and biomedical industries. PLA features poly(D-lactic acid) (PDLA) and poly(L-lactic acid) (PLLA) enantiomers, which form stereocomplex crystals through racemic blending. PLA emerged as a promising material owing to its sustainable, eco-friendly, and fully biodegradable properties. Nevertheless, PLA still has a low applicability for drug delivery as a carrier and scaffold. Stereocomplex PLA (sc-PLA) exhibits substantially improved mechanical and physical strength compared to the homopolymer, overcoming these limitations. Recently, numerous studies have reported the use of sc-PLA as a drug carrier through encapsulation of various drugs, proteins, and secondary molecules by various processes including micelle formation, self-assembly, emulsion, and inkjet printing. However, concerns such as low loading capacity, weak stability of hydrophilic contents, and non-sustainable release behavior remain. This review focuses on various strategies to overcome the current challenges of sc-PLA in drug delivery systems and biomedical applications in three critical fields, namely anti-cancer therapy, tissue engineering, and anti-microbial activity. Furthermore, the excellent potential of sc-PLA as a next-generation polymeric material is discussed.     

Structural and thermal properties of spray-dried methotrexate-loaded biodegradable microparticles

Drug–polymer interactions, structural properties, thermal behavior, and stability of biodegradable microparticles are fundamental aspects in the developing of new polymeric drug delivery systems. In this study, poly (d,l-lactide-co-glycolide) (PLGA) microparticles containing methotrexate (MTX) were successfully obtained by spray drying. Scanning electronic microscopy, differential scanning calorimetry (DSC), thermogravimetry (TG), X-ray diffraction (XRD), and drug-loading efficiency were used to investigate the effect of drug–polymer ratio and its interactions, in a new MTX-loaded PLGA spray-dried microparticles. High levels of encapsulation efficiency (about 90 %) and a prevalent spherical shape were identified for different drug–polymer ratios used (9, 18, and 27 % m/m). The thermal analyses (DSC and TG) and XRD indicate that MTX is homogeneously distributed in the polymeric matrix, with a prevalent amorphous state in a stable molecular dispersion. Therefore, a correlation between drug content and the structural-thermal properties of drug-loaded PLGA microparticles was established using the thermal analysis data. The biodegradable microparticle leads to an increment of thermal stability of MTX, confirming that spray drying is an efficient process for obtaining MTX-loaded PLGA microparticles.     

Targeted polymeric therapeutic nanoparticles: design, development and clinical translation

Polymeric materials have been used in a range of pharmaceutical and biotechnology products for more than 40 years. These materials have evolved from their earlier use as biodegradable products such as resorbable sutures, orthopaedic implants, macroscale and microscale drug delivery systems such as microparticles and wafers used as controlled drug release depots, to multifunctional nanoparticles (NPs) capable of targeting, and controlled release of therapeutic and diagnostic agents. These newer generations of targeted and controlled release polymeric NPs are now engineered to navigate the complex in vivo environment, and incorporate functionalities for achieving target specificity, control of drug concentration and exposure kinetics at the tissue, cell, and subcellular levels. Indeed this optimization of drug pharmacology as aided by careful design of multifunctional NPs can lead to improved drug safety and efficacy, and may be complimentary to drug enhancements that are traditionally achieved by medicinal chemistry. In this regard, polymeric NPs have the potential to result in a highly differentiated new class of therapeutics, distinct from the original active drugs used in their composition, and distinct from first generation NPs that largely facilitated drug formulation. A greater flexibility in the design of drug molecules themselves may also be facilitated following their incorporation into NPs, as drug properties (solubility, metabolism, plasma binding, biodistribution, target tissue accumulation) will no longer be constrained to the same extent by drug chemical composition, but also become in-part the function of the physicochemical properties of the NP. The combination of optimally designed drugs with optimally engineered polymeric NPs opens up the possibility of improved clinical outcomes that may not be achievable with the administration of drugs in their conventional form. In this critical review, we aim to provide insights into the design and development of targeted polymeric NPs and to highlight the challenges associated with the engineering of this novel class of therapeutics, including considerations of NP design optimization, development and biophysicochemical properties. Additionally, we highlight some recent examples from the literature, which demonstrate current trends and novel concepts in both the design and utility of targeted polymeric NPs (444 references).     

聚己内酯在药物载体方面的研究进展

聚己内酯(poly-ε-caprolactone,PCL)是一种人工合成的聚酯类高分子材料,对人体无毒,具有良好的生物相容性、生物可降解性和无免疫原性。PCL还对其它聚合物具有良好的相容性,可以制备出多种性能优良的共聚物或共混物,因此PCL及其共聚物、共混物作为药物载体的研究受到国内外研究者的高度重视。此外,PCL因其在人体中的降解过程十分缓慢可作为药物控释材料,目前已经获得美国FDA的批准。本文将从聚己内酯的合成与改性及其各剂型在药物载体方面的研究进展进行综述。     

Zwitterionic polymers: Addressing the barriers for drug delivery

Nanocarriers play an important role in drug delivery for disease treatment. However, nanocarriers face a series of physiological barriers after administration such as blood clearance, nonspecific tissue/cell localization, poor cellular uptake, and endosome trapping. These physiological barriers seriously reduce the accumulation of drugs in target action site, which results in poor therapeutic efficiency. Although polyethylene glycol (PEG) can increase the blood circulation time of nanocarriers, its application is limited due to the “PEG dilemma”. Zwitterionic polymers have been emerging as an appealing alternative to PEG owing to their excellent performance in resisting nonspecific protein adsorption. Importantly, the diverse structures bring functional versatility to zwitterionic polymers beyond nonfouling. This review focuses on the structures and characters of zwitterionic polymers, and will discuss and summarize the application of zwitterionic polymers for drug delivery. We will highlight the strategies of zwitterionic polymers to address the physiological barriers during drug delivery. Finally, we will give some suggestions that can be utilized for the development of zwitterionic polymers for drug delivery. This review will also provide an outlook for this field. Our aim is to provide a comprehensive and systemic review on the application of zwitterionic polymers for drug delivery and promote the development of zwitterionic polymers.     

Recombinant protein-based polymers for advanced drug delivery

Advances in recombinant techniques have led to the development of genetically engineered polymers with exquisite control over monomer sequence and polymer length. The ability to study how precise structures correlate with function has provided opportunities for the utility of these polymers in drug delivery. Chemically derived and developed methods of synthesis have yielded many useful polymers for drug delivery to-date, including those currently used in patients. However they have drawbacks, including limitations involved in statistical characterization of conventional polymer synthetic techniques. Encoding at the genetic level and production of such recombinant polymers in organisms allow for precise order and accuracy of amino acid residues and production of monodisperse polymers with specific function and physicochemical properties. Research into elastin-like, silk-like, and silk-elastinlike protein polymers for example has led to the development of delivery systems based on natural motifs of structural proteins to take advantage of their physicochemical properties. Additionally, protein based polymers on other natural motifs and de novo designs are starting to produce promising constructs for drug and gene delivery applications where precise control over structure promises correlation with function and guides the development of new and improved constructs. Clinical applications based on recombinant polymers for delivery of bioactive agents have not been realized at this point. However lessons learned from fundamental research with these polymers can be used to guide design of safe and effective systems for use in the clinic. This tutorial review summarizes progress made in the design and utility of recombinant polymers in drug and gene delivery and discusses challenges and future directions of such polymers for this purpose.     

Biodegradable polymers in gene‐silencing technology

Small interfering RNAs (siRNAs) technology has shown great promise as a new class of therapeutics invention for treatment of cancer and other diseases. siRNA has been used extensively in blocking various genes and is presently being evaluated as a therapeutic for cancer and viral disease. Despite the excitement about this remarkable biological process for sequence specific gene regulation, the major limitations against the use of siRNAs‐based therapeutics are their rapid degradation by serum nuclease, poor cellular uptake, and rapid renal clearance following systemic delivery, off‐target effects, and induction of immune responses. Many researchers have tried to overcome these limitations with developing nuclease‐resistant chemically modified siRNAs and variety of synthetic and natural biodegradable lipids and polymers for siRNA delivery to enhance efficacy and safety profiles. An ideal siRNAs‐based delivery system must be clinically suitable, safe, and effective. This review discuss the recent progress of biodegradable polymers in siRNA delivery technology.     

Encapsulation and sustained release of a model drug, indomethacin, using CO(2)-based microencapsulation

A carbon dioxide (CO(2))-based microencapsulation technique was used to impregnate indomethacin, a model drug, into biodegradable polymer nanoparticles. Compressed CO(2) was emulsified into aqueous suspensions of biodegradable particles. The CO(2) plasticizes the biodegradable polymers, increasing the drug diffusion rate in the particles so that drug loading is enhanced. Four types of biodegradable polymers were investigated, including poly(d,l-lactic acid) (PLA), poly(d,l-lactic acid-co-glycolic acid) (PLGA) with two different molar ratios of LA to GA, and a poly(d,l-lactic acid-b-ethylene glycol) (PLA-PEG) block copolymer. Biodegradable nanoparticles were prepared from polymer solutions through nonsolvent-induced precipitation in the presence of surfactants. Indomethacin was incorporated into biodegradable nanoparticles with no change of the particle size and morphology. The effects of a variety of experimental variables on the drug loadings were investigated. It was found that the drug loading was the highest for PLA homopolymer and decreased in PLGA copolymers as the fraction of glycolic acid increased. Indomethacin was predicted to have higher solubility in PLA than in PLGA based on the calculated solubility parameters. The drug loading in PLA increased markedly as the temperature for impregnation was increased from 35 to 45 degrees C. Drug release from the particles is a diffusion-controlled process, and sustained release can be maintained over 10 h. A simple Fickian diffusion model was used to estimate the diffusion coefficients of indomethacin in the biodegradable polymers. The diffusion coefficients are consistent with previous studies, suggesting that the polymer properties are unchanged by supercritical fluid processing. Supercritical CO(2) is nontoxic, easily separated from the polymers, can extract residual organic solvent, and can sterilize biodegradable polymers. The CO(2)-based microencapsulation technique is promising for the production of drug delivery devices without the use of harmful solvents.     

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.