Polymeric micelles for drug delivery: from synthesis to in vivo studies

Abstract

Drug delivery systems have been extensively utilized to increase water-solubility of hydrophobic chemotherapeutic drugs and target the drugs to tumors, which enhances the efficacy of chemotherapy and simultaneously decreases non-specific disposition of cytostatic drugs in healthy organ/tissues, and consequently avoids or minimizes toxicity/adverse effects. Among different nano-sized drug delivery systems, polymeric micelles are one of the most successful formulations applied on anti-cancer drugs, as evidenced from the fact that several micellar formulations for chemotherapeutic drugs have entered clinical trials. Polymeric micelles are extensively utilized for this purpose for the following reasons: (1) polymeric micelles possess a hydrophobic core suitable to accommodate hydrophobic (anti-cancer) compounds; (2) the hydrophilic micellar corona can provide ‘stealth’ properties and avoid their rapid removal by the reticuloendothelial system (RES); (3) polymeric micelles have a substantially lower critical micelle concentration (CMC) and therefore a better stability compared to micelles composed of small molecule surfactants; (4) micelle-forming polymers can be chemically tailored to increase the stability of polymeric micelles by introducing physical/chemical interactions between the polymer chains; (5) stimuli-sensitive micelles can be developed which release their payloads upon a certain physical trigger or upon degradation at their site of action; (6) polymeric micelles can be decorated with targeting moieties, which may potentially improve the therapeutic response by an increased uptake of drug-loaded polymeric micelles by cancer cells. Although polymeric micelles are attractive systems for tumor-targeted drug delivery, several hurdles hamper their applicability. For example, many micellar systems suffer from low stability in the blood circulation, which causes fast elimination of drug-loaded polymeric micelles after systemic administration and severely limits the tumor targeting efficacy of the systems, which is one of the main issues that the work described in this thesis aimed to address. Furthermore, applications of polymeric micelles other than tumor-targeted drug delivery have been proposed, including polymeric micelles based imaging-guided drug delivery and photodynamic therapy. This aim of this thesis is to further advance polymeric micelles as tumor-targeted carrier systems regarding the following aspects: (1) enhance the stability of polymeric micelles and drug retention in the blood circulation by means of chemical/physical interactions between the micelle forming polymer chains; (2) investigate the possibilities for the synthesis of better defined amphiphilic polymers by controlled/living polymerization, i.e., Reversible Addition Fragmentation Chain Transfer (RAFT) polymerization; (3) validate the concept of image-guided drug delivery based on fluorescently-labeled polymeric micelles; (4) study the pharmacokinetics, biodistribution and therapeutic efficacy of stabilized polymeric micelles in tumor models; (5) investigate the suitability of polymeric micelles for photodynamic therapy.