Introduction

Polymeric micelles are core/shell structures formed through the self-assembly of amphiphilic block copolymers. The nanoscopic dimension as well as unique properties offered by separated core and shell domains in the structure of polymeric micelles has made them one of the most promising carriers for passive or active drug targeting in cancer. The nanoscopic size of polymeric micelles makes the carrier unrecognizable by the phagocytic cells of the reticuloendothelial system (RES), elongating their blood circulation, and facilitating the carrier's extravasation from tumor vasculature. The small size of polymeric micelles is also expected to ease penetration of the carrier within the tumor tissue and further internalization of polymeric micelles into the tumor cells. Hydrophobic core of polymeric micelles provides an excellent host for the incorporation and stabilization of anticancer agents that are mostly hydrophobic. Steric effect induced by the dense hydrophilic brush on the micellar surface protects the carrier against attachment of proteins on the micellar surface, avoiding early uptake and clearance of the carrier by RES leading to prolonged circulation time and higher accumulation of the carrier and the encapsulated drug in selective tissues that have leaky vasculature (e.g., tumor or inflammation sites). Polymeric micelles have been the focus of several reviews in recent years.1-11

Among different micelle-forming block copolymers developed to date, those with polyethylene oxide) (PEO) as the shell-forming block and poly(L-amino acid)s (PLAA)s and poly(ester)s as the core-forming block are in the front line of drug development. The placement is owed to the biocompatibility of the PEO and biodegradability of PLAA and poly(ester) structures. The primary advantage of PEO-b-PLAA block copolymers over PEO-b-poly(esters) is the chemical flexibility of the PLAA structure that makes nano-engineering of the carrier a feasible approach.4 To date, research on PEO-b-PLAA for drug delivery has been mainly conducted on amino acids with functional side groups in their chemical structure, including L-aspartic acid, L-glutamic acid, L-lysine, and L-histidine. The presence of free functional side groups on the PLAA block provide sites for the attachment of drugs, drug compatible moieties, or charged therapeutics such as DNA. Moreover, a systemic alteration in the structure of the core-forming block also may be used to better control the extent of drug loading, release, or activation.

Chemical modifications in the structure of the PLAA block have led to the development of optimal PEO-b-PLAA-based polymeric micellar formulation for the delivery of a number of potent therapeutic agents, such as doxorubicin (DOX),12-23 paclitaxel (PTX),24 cisplatin (CDDP),25-32 amphotericin B (AmB),33-41 etc. To this point, three PEO-b-PLAA-based polymeric micellar formulations (all for the solubilization and delivery of anti-cancer agents) have successfully passed the phase of bench-top development and advanced to the stage of clinical evaluations

23 24 32

(Table 18.1).23,24,32 This chapter provides an overview on the preparation; micellar properties and biological performance of PEO-modified PLAA- based polymeric micellar formulations. Emphasis has been placed on the application of PEO-b-PLAA- micelles for the targeted delivery of anti-cancer agents. At the end, new advancements in the field, including a second generation of PEO-b-PLAA micelles (polymeric micelles for active targeting) and development of PEO-b-PLAA micelles for gene delivery are briefly discussed.

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