Abraham J. Domb

Biocompatibility and safety of PLA and its copolymers

PLA and its copolymers are commonly used for a wide variety of applications. While they are considered to be biocompatible, side effects resulting from their implantation have been reported. The implantation of biomaterials always results in a foreign body reaction. Such a reaction has also been reported following PLA and its copolymers. This article reviews the process of inflammatory reaction that is to be expected following implantation of PLA, and it highlights specific cases in which the inflammatory reaction can result in safety concerns. The authors also review selected cases from different medical fields to demonstrate possible clinical side effects resulting from its use.

Poly(lactic acid) Based Hydrogels.

Polylactide (PLA) and its copolymers are hydrophobic polyesters used for biomedical applications. Hydrogel medicinal implants have been used as drug delivery vehicles and scaffolds for tissue engineering, tissue augmentation and more. Since lactides are non-functional, they are copolymerized with hydrophilic monomers or conjugated to a hydrophilic moiety to form hydrogels. Copolymers of lactic and glycolic acids with poly(ethylene glycol) (PEG) provide thermo-responsive hydrogels. Physical crosslinking mechanisms of PEG-PLA or PLA-polysaccharides include: lactic acid segment hydrophobic interactions, stereocomplexation of D and L-lactic acid segments, ionic interactions, and chemical bond formation by radical or photo crosslinking. These hydrogels may also be tailored as stimulus responsive (pH, photo, or redox). PLA and its copolymers have also been polymerized to include urethane bonds to fabricate shape memory hydrogels. This review focuses on the synthesis, characterization, and applications of PLA containing hydrogels.

Injectable formulations of poly(lactic acid) and its copolymers in clinical use.

Poly(lactic acid) and its copolymers have revolutionized the field of drug delivery due to their excellent biocompatibility and tunable physico-chemical properties. These copolymers have served the healthcare sector by contributing many products to combat various diseases and for biomedical applications. This article provides a comprehensive overview of clinically used products of poly(lactic acid) and its copolymers. Multi-dimension information covering product approval, formulation aspects and clinical status is described to provide a panoramic overview of each product. Moreover, leading patented technologies and various clinical trials on these products for different applications are included. This review focuses on marketed injectable formulations of PLA and its copolymers.

Biodegradable polymers for targeted delivery of anti-cancer drugs

ABSTRACT Introduction: Biodegradable polymers have been used for more than three decades in cancer treatment and have received increased interest in recent years. A range of biodegradable polymeric drug delivery systems designed for localized and systemic administration of therapeutic agents as well as tumor-targeting macromolecules has entered into the clinical phase of development, indicating the significance of biodegradable polymers in cancer therapy. Areas covered: This review elaborates upon applications of biodegradable polymers in the delivery and targeting of anti-cancer agents. Design of various drug delivery systems based on biodegradable polymers has been described. Moreover, the indication of polymers in the targeted delivery of chemotherapeutic drugs via passive, active targeting, and localized drug delivery are also covered. Expert opinion: Biodegradable polymer-based drug delivery systems have the potential to deliver the payload to the target and can enhance drug availability at desired sites. Systemic toxicity and serious side effects observed with conventional cancer therapeutics can be significantly reduced with targeted polymeric systems. Still, there are many challenges that need to be met with respect to the degradation kinetics of the system, diffusion of drug payload within solid tumors, targeting tumoral tissue and tumor heterogeneity.

Preclinical Safety Evaluation in Rats of a Polymeric Matrix Containing an siRNA Drug Used as a Local and Prolonged Delivery System for Pancreatic Cancer Therapy.

Conventional chemotherapy treatments for pancreatic cancer are mainly palliative. RNA interference (RNAi)-based drugs present the potential for a new targeted treatment. LOcal Drug EluteR (LODERTM) is a novel biodegradable polymeric matrix that shields drugs against enzymatic degradation and releases small interfering RNA (siRNA) against G12D-mutated KRAS (siG12D). siG12D-LODER has successfully passed a phase 1/2a clinical trial. Such a formulation necessitates biocompatibility and safety studies. We describe the safety and toxicity studies with siG12D-LODER in 192 Hsd:Sprague Dawley rats, after repeated subcutaneous administrations (days 1, 14, and 28). Animals were sacrificed on days 29 and 42 (recovery phase). In all groups, no adverse effects were noted, and all animals showed favorable local and systemic tolerability. Histopathologically, LODER implantation resulted in the expected capsule formation, composed of a thin fibrotic tissue. On the interface between the cavity and the capsule, a single layer composed of macrophages and multinucleated giant cells was observed. No difference was noted between the placebo and siG12D-LODER groups. These findings provide valuable information for future preclinical studies with siRNA-bearing biodegradable polymers and for the safety aspects of RNAi-based drugs as a targeted therapy.

Stable polyanhydride synthesized from sebacic acid and ricinoleic acid.

ABSTRACT Poly(anhydride) are unstable and prone to hydrolytic degradation and depolymerisation via anhydride interchange. They are stored at − 20 °C, packed under inert atmosphere until use. We synthesized a new poly(anhydride) from ricinoleic (RA) and sebacic (SA) acid with alternating ester‐anhydride structure that is stable at 25 °C for over 18 months. The copolymer is also stable in chloroform solution and under &ggr;‐irradiation. The polymer hydrolyses through anhydride cleavage lasting ˜ 7 days to form oligoesters, which are stable for > 30 days. The release of gentamycin from the synthesized alternate polymer matrix is sustained compared to the random copolymer.

PEG-Biscyanoacrylate Crosslinker for Octyl Cyanoacrylate Bioadhesive

PEG400 (polyethylene glycol, MW 400) biscyanoacrylate is synthesized and copolymerized with 2-octyl cyanoacrylate for potential use as bioadhesive. PEG400 biscyanoacrylate is synthesized from the esterification of anthracenyl cyanoacrylic acid where the anthracene unit serves as vinyl-protecting group. Copolymerization increases the plasticity, mechanical strength, and resilience of the resulted polymer as determined by dynamic mechanical analysis. Peeling test confirms its superior bioadhesive properties. Surface morphology is characterized by SEM imaging. The formulations are cytocompatible and safe. This cyanoacrylate composition may provide improved bioadhesive cyanoacrylates.

Alternating Poly(ester-anhydride) by Insertion Polycondensation

We report on a synthetic method where polyanhydride is used as starting material and the ester monomers are inserted through complete esterification, leading to an alternating ester-anhydride copolymer. The molar ratio of ricinoleic acid (RA) and sebacic acid (SA) was optimized until polysebacic acid is completely converted to carboxylic acid-terminated RA-SA and RA-SA-RA ester-dicarboxylic acids. These dimers and trimers were activated with acetic anhydride, polymerized under heat and vacuum to yield alternating RA-SA copolymer. The resulting alternating poly(ester-anhydride) have the RA at regular intervals. The regular occurrences of RA side chains prevent anhydride interchange, enhancing hydrolytic stability, which allows storage of the polymer at room temperature.

Glycopeptides derived from glucosaminic acid

We report on the synthesis of polypeptides with saccharide side chains starting from D-gluconolactone. The resulting new non-ionic water soluble polymers, possessing the properties of peptides and saccharides, have potential uses as scaffolds for tissue engineering and drug carriers.