Polyacetal and poly(ortho ester)-poly(ethylene glycol) graft copolymer thermogels: preparation, hydrolysis and FITC-BSA release studies.

Graft copolymers comprised of a polyacetal backbone with pendant poly(ethylene glycol) side-chains were prepared using a condensation reaction between a divinyl ethers, a diol and Fmoc-protected serinol, followed by deprotecting the amine and reacting the polyacetal with pendant amino groups with PEG-alpha-methoxy-omega-succimidylcarbonate. A series of materials having lower critical solution temperature (LCST) between 25 and 60 degrees C has been prepared. Since LCST is determined by the hydrophilic-hydrophobic balance, and this in turn is determined by the molecular weight of the polyacetal backbone, the molecular weight of the grafted PEG and the amount grafted, materials having a desired LCST could be readily prepared.

Biochronomer technology.

Biochronomer (AP Pharma) is a fourth-generation poly(ortho ester) prepared by the condensation of diols and a diketene acetal. The polymer contains a copolymerised latent acid whose concentration controls erosion rate. The polymer has been shown to undergo a surface erosion process and a number of applications have been explored.

Ocular delivery using poly(ortho esters).

Three families of poly(ortho esters) were investigated as a means of delivering 5-fluorouracil (5-FU), an antiproliferative agent used as an adjunct to glaucoma filtering surgery. Release of 5-FU from a crosslinked POE II occurred predominantly by diffusion with little weight loss, while release of 5-FU from a linear polymer occurred by an erosion-controlled process confined predominantly to the surface layers. No ocular biocompatibility studies were carried out.

Poly(ortho esters)--from concept to reality.

The development of poly(ortho esters) dates back to the early 1970s, and during that time, four distinct families were developed. These polymers can be prepared by a transesterification reaction or by the addition of polyols to diketene acetals, and it is the latter method that has proven to be preferred one. The latest polymer, now under intense development, incorporates a latent acid segment in the polymer backbone that takes advantage of the acid-labile nature of the ortho ester linkages and allows control over erosion rates.

Molecularly engineered poly(ortho ester) microspheres for enhanced delivery of DNA vaccines.

Genetic vaccination using plasmid DNA presents a unique opportunity for achieving potent immune responses without the potential limitations of many conventional vaccines. Here we report the design of synthetic biodegradable polymers specifically for enhancing DNA vaccine efficacy in vivo. We molecularly engineered poly(ortho ester) microspheres that are non-toxic to cells, protect DNA from degradation, enable uptake by antigen-presenting cells, and release DNA rapidly in response to phagosomal pH.

Preparation, characterization, and in vitro evaluation of physostigmine-loaded poly(ortho ester) and poly(ortho ester)/poly(D,L-lactide-co-glycolide) blend microspheres fabricated by spray drying.

The physostigmine-loaded poly(ortho ester) (POE), poly(dl-lactide-co-glycolide) (PLGA) and POE/PLGA blend microspheres were fabricated by a spray drying technique. The in vitro degradation of, and physostigmine release from, the microspheres were investigated. SEM analysis showed that the POE and POE/PLGA blend particles were spherical.

Polyacetal-doxorubicin conjugates designed for pH-dependent degradation.

Terpolymerization of poly(ethylene glycol) (PEG), divinyl ethers, and serinol can be used to synthesize water soluble, hydrolytically labile, amino-pendent polyacetals (APEGs) suitable for drug conjugation. As these polyacetals display pH-dependent degradation (with faster rates of hydrolysis at acidic pH) and they are not inherently hepatotropic after intravenous (iv) injection, they have potential for development as biodegradable carriers to facilitate improved tumor targeting of anticancer agents. The aim of this study was to synthesize a polyacetal-doxorubicin (APEG-DOX) conjugate, determine its cytotoxicity in vitro and evaluate its potential for improved tumor targeting in vivo compared to an HPMA copolymer-DOX conjugate in clinical development.

Ocular biocompatibility of a poly(ortho ester) characterized by autocatalyzed degradation.

The biocompatibility of autocatalyzed poly(ortho ester) (POE(70)LA(30)), a viscous, hydrophobic, bioerodible polymer, was investigated. POE(70)LA(30) was synthesized, sterilized by gamma irradiation, and injected in rabbit eyes at adequate volumes through subconjunctival, intracameral, intravitreal, and suprachoroidal routes. Clinical examinations were performed postoperatively at regular time points for 6 mo, and histopathologic analysis was carried out to confirm tissular biocompatibility.

Double walled POE/PLGA microspheres: encapsulation of water-soluble and water-insoluble proteins and their release properties.

The poly(orthoester) (POE)-poly(D,L-lactide-co-glycolide) (50:50) (PLGA) double-walled microspheres with 50% POE in weight were loaded with hydrophilic bovine serum albumin (BSA) and hydrophobic cyclosporin A (CyA). Most of the BSA and CyA was entrapped within the shell and core, respectively, because of the difference in their hydrophilicity. The morphologies and release mechanisms of proteins-loaded double-walled POE/PLGA microspheres were investigated.

POE/PLGA composite microspheres: formation and in vitro behavior of double walled microspheres.

The poly(ortho ester) (POE) and poly(D,L-lactide-co-glycolide) 50:50 (PLGA) composite microspheres were fabricated by a water-in-oil-in-water (w/o/w) double emulsion process. The morphology of the composite microspheres varied depending on POE content. When the POE content was 50, 60 or 70% in weight, the double walled microspheres with a dense core of POE and a porous shell of PLGA were formed.

Post surgical pain management with poly(ortho esters).

Poly(ortho esters), POE, are synthetic bioerodible polymers that can be prepared as solid materials, or as viscous, injectable polymers. These materials have evolved through a number of families, and the latest member of this family, POE IV, is particularly well suited to drug delivery since latent acid is integrated into the polymer backbone, thereby, modulating surface erosion. POE IV predominantly undergoes surface erosion and is able to moderate drug release over periods from days to many months.

Poly(ortho esters): synthesis, characterization, properties and uses.

Over the last 30 years, poly(ortho esters) have evolved through four families, designated as POE I, POE II, POE III and POE IV. Of these, only POE IV has been shown to have all the necessary attributes to allow commercialization, and such efforts are currently underway. Dominant among these attributes is synthesis versatility that allows the facile and reproducible production of polymers having the desired mechanical and thermal properties as well as desired erosion rates and drug release rates that can be varied from a few days to many months.

Semisolid, self-catalyzed poly(ortho ester)s as controlled-release systems: protein release and protein stability issues.

Semisolid, self-catalyzed poly(ortho ester)s (POEs), are investigated as potential sustained-release systems for proteins. In this study, some factors influencing protein release kinetics and protein instability were evaluated. As model proteins, lysozyme, alpha-lactalbumin, bovine serum albumin, and vascular endothelial growth factor, which were lyophilized from various buffer solutions in the absence and presence of lyoprotectants, were used.

Development of poly(ortho esters) and their application for bovine serum albumin and bupivacaine delivery.

The preparation of drug delivery devices using solventless fabrication procedures is of significant interest and two such procedures are described. In one such procedure, powdered polymer and micronized protein are intimately mixed and then extruded into 1 mm strands that are cut to the desired length. The polymers used were specifically designed to allow extrusion at temperatures where proteins maintain activity in the dry state.