The use of conventional formulations for the systemic administration of many small molecule anticancer agents often results in an unsatisfactory therapeutic effect because of the narrow therapeutic window of these drugs. The low therapeutic index of these drugs is mostly attributed to the dose-limiting toxicities that are associated with them and/or the excipients used in the formulation. Therefore, colloidal carriers that are composed of biocompatible and biodegradable materials with sustained drug release have been developed for formulation and delivery. Nanosized colloidal carriers have been shown to allow for increased accumulation of drug at tumors via the enhanced permeation and retention (EPR) effect.1 As a result of the altered pharmacokinetics, the exposure of chemotherapeutic drugs to healthy tissues is reduced. Colloidal carriers including liposomes, nanoparticles, and polymeric micelles have been explored extensively for the delivery of a wide range of drugs as anti-cancer therapy.1,2

Polymeric micelles are nanosized assemblies of amphiphilic block copolymers that are suitable for the delivery of hydrophobic and amphiphilic agents. In an aqueous medium, micelles consist of a hydrophilic shell that minimizes clearance by the mononuclear phagocytic system (MPS) and a hydrophobic core that functions as a reservoir for hydrophobic drugs. In the past two decades, four polymeric micelle formulations loaded with chemotherapeutic drugs (i.e., NK911, SP1049C, Genexol-PM, and NK105) have entered clinical trial development. The results from the clinical studies have indicated that the polymeric micelle formulations reduce the toxicity associated with conventional formulations of these drugs that, in turn, results in a higher therapeutic index. Many preclinical fundamental studies have evaluated the relationships between the composition of the copolymers and the physico-chemical properties of the micelles. The properties of the micelles such as polymer-drug compatibility, thermodynamic and kinetic stability, and the drug release profiles have been shown to influence the in vivo performance and therapeutic effectiveness of the micelle-formulated drugs. These studies serve as guidelines for the optimization of polymeric micelles for clinical applications.

This chapter is divided into six major sections and provides a discussion of the various aspects relating to use of polymeric micelles for formulation of anti-cancer drugs. Section 17.2 contains information on the physico-chemical properties of micelles (e.g., composition, size and size distribution, morphology, stability), micelle preparation techniques as well as drug loading and release properties of micelles. Section 17.3 highlights the preclinical development of several polymeric micelle formulations that are currently under clinical trial evaluation for use as cancer therapy. Specifically, the optimization of the physico-chemical characteristics of NK911, SP1049C, Genexol-PM, and NK105 are discussed. In Section 17.4, the interaction between polymeric micelles and cancer cells, including cellular internalization, in vitro cytotoxicity, and chemosensitization of multi-drug resistant (MDR) cancer cells is reviewed. In Section 17.5, the physico-chemical properties of polymeric micelles are related to their in vivo performance such as in vivo drug release, pharmacokinetics, toxicity profiles, and anti-cancer efficacy. Finally, in Section 17.6, the development of several advanced polymeric micelle systems that are capable of targeted delivery to tumors via external stimuli (e.g., ultrasound, heat, light) or active targeting mechanisms (e.g., ligand coupling, pH-sensitive) are introduced.

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