Therefore, we undertook the present study to determine ( a) whether polilactofate microspheres were biocompatible in the CNS and ( b) whether they could deliver therapeutic levels of paclitaxel to CNS malignancies.
Nevertheless, in vitro assays demonstrate that brain tumor cell lines are sensitive to paclitaxel, indicating that clinical responses may be possible if adequate CNS paclitaxel concentrations can be achieved (12, 13, 14).
Unfortunately, paclitaxel has failed multiple clinical trials against malignant brain tumors because even at maximally tolerated systemic doses, levels in the CNS are low to undetectable (4, 11). Paclitaxel has been clinically effective against a variety of human cancers, including ovarian and breast cancer, and has been used in conjunction with polilactofate microspheres in animal models of non-small cell lung cancer (3). Paclitaxel, an antimicrotubule, antineoplastic agent, was evaluated in conjunction with the polilactofate matrix based on these physical properties (Paclimer Delivery System). Because the microsphere formulation of the polilactofate polymer provides a large surface area for hydrophobic degradation of the polymer, polilactofate microspheres are particularly suitable for delivery of high molecular weight, highly hydrophobic compounds that are released slowly or minimally from existing controlled-release matrices such as PCPP-SA. Polilactofate microspheres consist of a polyphosphoester polymer backbone that undergoes hydrolytic degradation in an aqueous environment, releasing drug encapsulated within the microspheres. In this report we describe another biodegradable, controlled-release, polymeric microsphere construct that is biocompatible in the CNS and extends the types of compounds that can be delivered intracranially in vivo. One of the formulations, PCPP-SA impregnated with the nitrosourea carmustine, has been used successfully for treatment of malignant brain tumors and became the first United States Food and Drug Administration-approved therapy for this disease in 23 years (2). Recently, biodegradable, controlled-release, polymeric formulations have been developed that can be surgically implanted into a tumor, bypassing the blood-brain barrier (1). Tight junctions unique to cerebral endothelial cells exclude most pharmaceutical agents that are not able to diffuse across their lipid bilayer. The blood-brain barrier is a major obstacle to developing effective pharmacological treatments for CNS 4 malignancies. Rats implanted with Paclimer demonstrated no overt signs of neurotoxicity and exhibited local cytopathological changes consistent with exposure to an antimicrotubule agent.Ĭonclusions: Paclimer extends survival in a rodent model of glioma with minimal morbidity and optimal pharmacokinetics. Active drug was distributed throughout the rat brain based on liquid scintillation counting and TLC. In vivo, Paclimer implants placed intracranially in rats released active drug for up to 30 days after implantation and doubled the median survival of rats bearing established 9L gliosarcomas (median survival of paclitaxel-treated animals = 35 days median survival of control-treated animal = 16 days P < 0.0001). Results: Paclimer released paclitaxel at a constant rate for up to 3 months in vitro. Paclimer implants tagged with paclitaxel were used to measure biodistribution of paclitaxel from the Paclimer implant.
Mantel-Cox statistics were used to assess the efficacy of Paclimer at extending survival of tumor-bearing animals compared with control implants. In vivo studies of Paclimer were performed as intracranial implants in Fischer 344 rats in the presence or absence of 9L gliosarcoma. Purpose: The purpose of this study was to demonstrate that surgically implanted, controlled-release, biodegradable polilactofate microspheres (Paclimer) can be used safely to bypass the blood-brain barrier and deliver paclitaxel to malignant brain tumors.Įxperimental Design: The rate of paclitaxel release from Paclimer microspheres submerged in PBS was measured in vitro by high-performance liquid chromatography.
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