Biocompatible poly(methylidene malonate)-made materials for pharmaceutical and biomedical applications.

In the past 20 years, mainly with the sponsorship of Laboratoires UPSA (France) and, afterwards, its spin-off company Virsol (France), several authors have studied methylidene malonate-based polymers used in drug delivery approaches and in the development of novel biomaterials. The present paper aims at summing up the preparation of methylidene malonate monomers, and essentially a novel asymmetric diester structure: 1-ethoxycarbonyl-1-ethoxycarbonylmethylenoxycarbonyl ethene named methylidene malonate 2.1.2. Their polymeric and copolymeric derivatives and a few of their applications which were reported in the literature are also presented. It encompasses the manufacturing of particulate systems such as nano- and macroparticles designed for the delivery of hydrophilic or hydrophobic drugs and biomolecules. This review article also describes their use as biomaterials of interest in the fields of tissue repair, as drug reservoirs or ophthalmology, as implants. Copolymers based on these monomers offer a large range of properties and could be used as new surfactants, micellar vectors, or particulate systems for gene delivery. Therefore, this review, certainly the first dedicated exclusively to methylidene malonate-based materials, highlights the great biomedical and pharmaceutical technology potential of these new materials.

The brain tissue response to biodegradable poly(methylidene malonate 2.1.2)-based microspheres in the rat.

The aim of this study was to follow the in vivo biodegradation as well as to appreciate the brain tissue response to poly(methylidene malonate 2.1.2) (PMM 2.1.2)-based microspheres implanted into the rat brain. Ninety-three adult Sprague-Dawley female rats were engaged in the study in which 54 underwent stereotactic implantation of blank gamma-sterilized PMM 2.1.2-based microspheres, prepared by an emulsion-extraction method. Twelve rats were implanted with the same 5-fluorouracil (5-FU)-loaded microspheres. Seventeen controls received the suspension medium alone (carboxymethylcellulose aqueous solution). The animals were sacrificed on post-operative days 1, 2, 8 and months 1, 2, 3, 6, 9, 12, 15 and 18. The brains were dissected, frozen, cut in a freezing microtome, and the slides were processed for immunohistological evaluation and scanning electron microscopy. During the first few days, the moderate inflammatory response to blank or loaded PMM 2.1.2 microspheres was largely a consequence of the mechanical trauma that occurs during surgery. The macrophagous-microglial reaction was similar to the one typically found following any damage in the CNS. There were also no differences in GFAP reactivity between the implanted animals and the controls. Blank microspheres began to degrade between 3 and 6 months, while 5-FU microspheres degraded between 8 days and 1 month. The polymer degradation generated in both cases a pronounced inflammatory and immunological reaction, leading to an important cell loss, a cerebral atrophy and to the death of several animals. PMM 2.1.2 was thus shown to be inadequate for intracerebral drug delivery.

Development of novel 5-FU-loaded poly(methylidene malonate 2.1.2)-based microspheres for the treatment of brain cancers.

In order to treat malignant brain tumors by local delivery of antineoplastic agents, the feasibility of 5-fluorouracil (5-FU)-sustained release biodegradable microspheres with a novel material, poly(methylidene malonate 2.1.2), was investigated using an emulsion/extraction method. This polymer was expected to present a slow degradation rate, thus leading to a long term local delivery system. Microparticles were successfully obtained and characterized in terms of drug loading, size, morphology and release profile. The size of the particles was between 40 and 50 microm, which was compatible with a stereotactic injection through a needle. Sufficient drug loadings were obtained (i.e. compatible with the preparation of therapeutic 5-FU doses in a minimal volume of injection), and perfectly spherical microspheres were observed. The respective influences of the polymer molecular weight, the polymer concentration, and the emulsion time on the release profiles were studied using a 2(3) factorial design. In the same objective, the solvent extraction time was extended while keeping all the previous parameters fixed at their optimal values. The in vitro study of these different parameters allowed a reduction of the initial burst release, with a percentage of 5-FU released after 24 h that was lowered from 90 to 65%, and the achievement of a long term drug delivery system, since the release was still ongoing after 43 days. Moreover, the microparticles could be gamma-sterilized (25 kGy) without modification of the release kinetics. Thus, the requested specifications to perform animal experiments were attained.

Therapeutic effectiveness of novel 5-fluorouracil-loaded poly(methylidene malonate 2.1.2)-based microspheres on F98 glioma-bearing rats.

BACKGROUND: Drug delivery to the central nervous system (CNS) remains a real challenge for neurosurgeons and neurologists, because many molecules cannot cross the blood-brain barrier (BBB). In recent years, solid polymeric materials have been implanted into animal and human brains either by surgery or using stereotactic methods to assure the controlled release of a drug over a determined period, thus circumventing the difficulties posed by the BBB. Poly(methylidene malonate 2.1.2) (PMM 2.1.2) is a new polymer that was described a few years ago and that allows the fabrication of novel, 5-fluorouracil (5-FU)-loaded PMM 2.1.2 microspheres. The objective of the current study was to assess the therapeutic effectiveness of those particles in a rat brain tumor model, the F98 glioma. METHODS: Forty-three rats were used in this study. First, a histologic evaluation of the F98 tumor model was performed on Fischer female rats. Thereafter, different groups of rats were injected and were treated with 5-FU microspheres in 2 different suspension media: carboxymethylcellulose (CMC) aqueous solution with or without 5-FU. RESULTS: The tumor was confirmed as extremely aggressive and invasive, even in early development. The 5-FU-loaded microspheres improved rat median survival significantly compared with untreated animals, CMC-treated animals, and 5-FU solution-treated animals when injected in CMC without 5-FU, demonstrating the interest of a sustained release and the efficacy of intratumoral chemotherapy against an established tumor. CONCLUSIONS: PMM 2.1.2 microspheres appeared to be a promising system, because their degradation rate in vivo was longer compared with many polymers, and they may be capable of long-term delivery.