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Abstract: In this study, we aimed at developing controlled and sustained protein release formulations using a combination system of polyelectrolyte complexes (PECs) and thermosensitive poly(organophosphazene) hydrogels as an injectable gel-depot system. In the protein-loaded hydrogel system, the loaded proteins were released rapidly through diffusion regardless of viscosities and mass loss of the gels because of the small hydrodynamic size of the proteins. To suppress protein diffusion and increase protein size, we induced PECs between negatively charged proteins (BSA, gelatin-type B 75 bloom, α-amylase, and hGH) and polycations (protamine, polyethylenimine, poly-l-lysine, and poly-l-arginine (PLA)) via an electrostatic interaction and loaded the PECs into the hydrogels. The formations of PECs were affected by molecular weight, pI (or pK a), and types of amine group of the used polycations. Unlike other polycations, PLA formed a large uniform complex with BSA, and the PLA/protein complex-loaded hydrogel showed the slowest protein release behavior. In the PEC-loaded hydrogel system, the protein release could also be controlled by viscosities of the gel and weight ratios of polycations and proteins, although the activities of the proteins were decreased in proportion to the PLA amounts. These results suggest that the PEC-loaded injectable and thermosensitive poly(organophosphazene) hydrogel has considerable potential for creating a sustained protein delivery system by using the PEC via electrostatic interaction. [ABSTRACT FROM AUTHOR]

Abstract: Poly(organophosphazenes) have been suggested as a potential thermosensitive hydrogel for use in the development of an injectable gel-depot system. Under biological conditions, hydrophilic model protein drugs, including bovine serum albumin (BSA), gelatin type B (MW 20,000) (GB20), and fluorescein isothiocyanate albumin (FITC-albumin) loaded in the hydrogels were released for 1–2 weeks, showing an initial burst release. However, this initial burst release could be suppressed when the proteins were couched in a complex with chitosan, and under these conditions evidenced a prolonged release period. BSA, GB20, and FITC-albumin, all of which are negatively charged at a pH of 7.4, interacted with chitosan harboring positive amine groups. The formation of these protein/chitosan complexes were confirmed via measurements of changes in zeta-potential and high-performance liquid chromatography. We determined the appropriate ratio of proteins to chitosan for suppression of the initial burst to be 1:5 to 1:10. From these findings, we were able to conclude that both the release rate and release period could be controlled via the formation of protein/chitosan complex. [Copyright &y& Elsevier]

Abstract: Thermosensitive poly(organophosphazenes) bearing hydrophobic isoleucine ethyl esters group and hydrophilic α-amino-ω-methoxy-poly(ethylene glycol) of the molecular weight 550 along with hydrolysis-sensitive glycyl lactate ethyl esters have been synthesized for sustained delivery of anticancer drug. The aqueous solution of poly(organophosphazenes) containing doxorubicin, that represents chemotherapeutic agent for cancer treatment, was transformed into hydrogel with good gel strength at body temperature via hydrophobic interactions. Solubility of hydrophobic doxorubicin in the aqueous poly(organophosphazene) solution was dramatically improved as compared with that in PBS (0.01M, pH 7.4). The hydrogel property of poly(organophosphazenes) was affected on incorporation of doxorubicin, resulting in increase of gelation temperature and decrease of gel strength. The release of loaded doxorubicin from the polymer hydrogel was significantly sustained over 20 days and the effect of gel strength, polymer concentration and drug concentration on the release rate were observed. The release of doxorubicin from the polymer gels was effectively controlled by the gel strength. As a result of investigating anticancer efficacy using cancer cell line of mouse lymphoblast of P388D1, the efficacy of doxorubicin was observed to be constant over a prolonged period of times for more than 30 days, indicating that the release of doxorubicin was sustained for a long time without any initial burst release, and that the delivery system was an excellent candidate for locally injectable gel–depot system. [Copyright &y& Elsevier]

This review reports research carried out by the authors during the last 10 years. The research involves the synthesis, characterization, functionalization, and possible utilization of cyclo- and polyphosphazenes. The investigations concern the synthesis of poly(dichlorophosphazene) by polycondensation reaction of dichlorophinoyliminotrichlorophosphorane; the grafting of unsaturated organic substrates (maleic anhydride, maleates or vinyl polymers) onto poly(organophosphazenes) by free radical reactions and the use of the synthesized materials for the preparation of new grafted copolymers or for the superficial modification of conventional organic macromolecules; the synthesis of phosphazenes containing free hydroxylic groups by reaction of methoxy aryloxy- or methoxy oligoethyleneoxy-substituted cyclo- and polyphosphazenes with boron tribromide or trimethylsilyl iodide and their use for the preparation of new phosphazene-based materials (e.g., sol-gel hybrids, thermosetting resins, azodyes, cyclolinear inorganic–organic polymers sometimes containing chiral units, or organic macromolecules having cyclophosphazene residues as pendant groups); and the preparation of oxazoline-containing cyclic and polymeric phosphazene derivatives for the synthesis of photoinitiators, chain extenders, or blend compatibilizers. The possible developments of this research are also envisaged. [ABSTRACT FROM AUTHOR]

The synthesis of a new, highly photosensitive, phosphazene copolymer containing an almost-equimolecular quantity of benzophenone and methoxyethoxyethoxy substituents is reported in this paper, together with the photochemical behavior of this material when irradiated in film both in oxygen and in an argon atmosphere. It has been detected that the photoreactivity of the phosphazene material strongly depends on the light absorption process by the benzophenone moieties, whose selective excitation predominantly brings about an intramolecular hydrogen abstraction reaction from the ethylene oxide units, thus producing highly reactive phosphazene macroradicals. The coupling reactions of these species results in the complete cross-linking of the polyphosphazene substrate and in its total insolubilization. Moreover, the influence of molecular oxygen on the overall photochemical process of the benzophenone/ethyleneoxide-substituted phosphazene copolymer is investigated. The implications of the light-induced reticulation process in the controlled insolubilization of poly[ bis (methoxyethoxyethoxy)phosphazene] are also discussed. [ABSTRACT FROM AUTHOR]