| |
[摘要]：Oral administration of anticancer agents is preferred by patients for its convenience and potential for use in outpatient and palliative setting. in addition, oral administration facilitates a prolonged exposure to the cytotoxic agents. Enhancement of bioavailability of emerging cytotoxic agents is a pre-requisite for successful development of oral modes of cancer treatment. Over the last decade, our studies have focused specifically on the utilization of large (MW > 10(5)) and non-degradable polymers in oral chemotherapy. A family of block-graft copolymers of the poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) Pluronic (R) polyethers and poly(acrylic acid) (PAA) bound by carbon-carbon bonds emerged, wherein both polymeric components are generally recognized as safe. Animal studies with Pluronic-PAA copolymers demonstrated that these molecules are excreted when administered orally and do not absorb into the systemic circulation. The Pluronic-PAA copolymers are surface-active and self-assemble, at physiological pH, into intra- and intermolecular micelles with hydrophobic cores of dehydrated PPO and multilayered coronas of hydrophilic PEO and partially ionized PAA segments. These micelles efficiently solubilize hydrophobic drugs such as paclitaxel and steroids and protect molecules such as camptothecins from the hydrolytic reactions. High surface activity of the Pluronic-PAA copolymers in water results in interactions with cell membranes and suppression of the membrane pumps such as P-glycoprotein. The ionizable carboxyls in the micellar corona facilitate mucoadhesion that enhances the residence time of the micelles and solubilized drugs in the gastrointestinal tract. Large payloads of the Pluronic-PAA micelles with weakly basic and water-soluble drugs such as doxorubicin and its analogs, mitomycin C, mitoxantrone, fluorouracil, and cyclophosphamide are achieved through electrostatic interactions with the micellar corona. Mechanical and physical properties of the Pluronic-PAA powders, blends, and micelles allow for formulation procedures where art active is simply dispersed into an aqueous Pluronic-PAA micellar formulation followed by optional lyophilization and processing into a ready dosage form. We review a number of in vivo and in vitro experiments demonstrating that that the oral administration of the cytotoxics formulated with the Pluronic-PAA copolymer micelles results in enhanced drug bioavailability. (C) 2008 Elsevier B.V. All rights reserved. |
|
