Polymeric Micelles and Dendritic Amphiphiles for the Anticancer Drug Sagopilone: Solubilization, Formulation Development, and Toxicity Assessment

The present thesis describes the study of polymeric micelles and novel dendritic amphiphiles for the solubilization and parenteral administration of Sagopilone, a novel anticancer drug. Suitable colloidal carriers were identified and characterized in terms of solubilization, stability, formulation feasibility, and toxicity. Chapter 2 describes the systematic study of polymeric micelles using PEG-b-PLA (poly(ethylene glycol)-b-poly(lactide)) and PEG-b-PCL (poly(ethylene glycol)-b-poly(ε-caprolactone)) block copolymers as drug delivery systems for Sagopilone. PEG2000-b-PDLLA2200, PEG2000-b-PCL2600, and PEG5000-b-PCL5000 were identified as being most suitable in terms of efficient solubilization and stability. The corresponding micelles were shown to be small, monodisperse, spherical micelles. Contrary to previous reports, calculated solubility parameters were not predictive since they showed a reversed order of preference relative to experimental data, and the substantial difference in the solubilization capacity of the two stereoisomers of PLA was not covered. ‘Supersaturation’ is a preparation-specific phenomenon following film formation. Its cause as well as the solubilization of Sagopilone within the block copolymer films were elucidated by the evidence of glass solutions that exceeded the solubilization capacity of the corresponding micelles in terms of Sagopilone content. The apparent solid-state saturation solubility of Sagopilone in the block copolymer was determined using the Couchman-Karasz approach and showed a good correlation with the loading capacity of the respective micelles. Chapter 3 describes the stability investigations of the resulting polymeric micelles, novel formulation approaches, and the toxicity testing in vitro as well as in vivo. Although the micelles exhibited a similar thermodynamic stability, PEG-b-PCL micelles were kinetically more stable than P2LA(1.1) prior to and after further dilution as well as at elevated temperatures. Lyophilization of PEG-b-PCL micelles was shown to be feasible in the presence of additional excipients that prevent PCL crystallization. The feasibility of Sagopilone loaded polymeric films of P2LA(1.1) for redispersion later on was demonstrated for the first time and the storage temperature was identified as the key stability parameter. In vitro, Sagopilone loaded polymeric micelles were equipotent to Sagopilone cyclodextrin-based reference solutions using a cervix carcinoma cell line. In vivo, no carrier-associated side effects were observed, and the maximum tolerated dose (MTD) of micellar Sagopilone was determined to be 6 mg/kg using nude mice. However, the latter was decreased compared to a cyclodextrin-based formulation of Sagopilone possibly due to a hampered drug degradation by serum esterases resulting in an enhanced effective dose. Overall, these results highlight that polymeric micelles, especially PEG-b-PCL micelles, fulfil key requirements for their use in parenteral formulations. In particular, they offer an excellent potential for further preclinical and clinical cancer studies using Sagopilone. Chapter 4 describes structure-response relationship investigations of novel dendritic glycerol-based amphiphiles in terms of Sagopilone solubilization, micelle stability, and cytotoxicity. These amphiphiles are composed of a hydrophilic headgroup composed of dendritic polyglycerol coupled to an alkyl chain (C18) and various hydrophobic modifications. They showed superior solubilization capacities of Sagopilone compared to standard excipients used in parenteral formulations. Looking at their different core structures, the best solubilization was achieved with a diaromatic spacer group. This indicates that the hydrophobic-hydrophilic interface of the micelles is the main locus of drug solubilization. They showed an excellent formulation stability profile both undiluted and after dilution independent of their core structure, which is another important requirement for novel solubilizers. Cytotoxicity testing in primary endothelial cells revealed the least toxicity in the presence of a naphthyl end group with values comparable to Cremophor® EL and polysorbate 80. Overall, these results highlight the potential offered by these novel dendritic amphiphiles.