ABSTRACT

Currently, the limiting factor in cancer chemotherapy is the lack of selectivity of anticancer drugs toward neoplastic cells. Generally, rapidly proliferating cells such as those of the bone marrow or the gastrointestinal tract are affected by the cytotoxic action of these drugs. This results in a narrow therapeutic index of most anticancer compounds. Furthermore, the emergence of resistant cell sublines during the chemotherapeutic treatment may require the use of higher doses of anticancer drugs or the elaboration of dosing protocols combining different anticancer drugs. This, in return, may enhance the toxicity of the treatment. To decrease the toxicity and to enhance the selectivity of existing drugs, many drug delivery systems have been developed in recent years (1,2). These systems include soluble drug-polymer conjugates, polymeric micelles, nanoparticles (NP), liposomes, and microparticles (3-8). NP are attracting increased attention and growing interest for drug targeting, because they can be easily prepared with well-defined biodegradable polymers (9). In the first studies, the rationale behind using NP for cancer therapy was based on the fact that certain neoplastic cells have been found to exhibit an enhanced endocytotic activity (10). Recent studies have shown that encapsulating chemotherapeutic agents in NP can also influence pharmacokinetic parameters and the biodistribution of the drug. Therefore, it is expected to help tumor accumulation with a resulting limitation of the adverse effects. High concentration in neoplastic tissues can be obtained based on peculiarities of the vascular system surrounding tumors. Indeed, the vascular system of tumors is highly disorganized and presents an enhanced permeability due to the tumor-increased needs in oxygen and nutrients. This phenomenon called the enhanced permeability and retention (EPR) effect provides an interesting gateway for small NP to penetrate more readily into tumoral sites (11-13). This retention effect is further potentialized by an impaired lymphatic drainage reducing carrier clearance from the tumor.