Injectable diblock copolypeptide hydrogel provides platform to deliver effective concentrations of paclitaxel to an intracranial xenograft model of glioblastoma.

INTRODUCTION: Surgical resection and systemic chemotherapy with temozolomide remain the mainstay for treatment of glioblastoma. However, many patients are not candidates for surgical resection given inaccessible tumor location or poor health status. Furthermore, despite being first line treatment, temozolomide has only limited efficacy. METHODS: The development of injectable hydrogel-based carrier systems allows for the delivery of a wide range of chemotherapeutics that can achieve high local concentrations, thus potentially avoiding systemic side effects and wide-spread neurotoxicity. To test this modality in a realistic environment, we developed a diblock copolypeptide hydrogel (DCH) capable of carrying and releasing paclitaxel, a compound that we found to be highly potent against primary gliomasphere cells. RESULTS: The DCH produced minimal tissue reactivity and was well tolerated in the immune-competent mouse brain. Paclitaxel-loaded hydrogel induced less tissue damage, cellular inflammation and reactive astrocytes than cremaphor-taxol (typical taxol-carrier) or hydrogel alone. In a deep subcortical xenograft model of glioblastoma in immunodeficient mice, injection of paclitaxel-loaded hydrogel led to local tumor control and improved survival. However, the tumor cells were highly migratory and were able to eventually escape the area of treatment. CONCLUSIONS: These findings suggest this technology may be ultimately applicable to patients with deep-seated inoperable tumors, but as currently formulated, complete tumor eradication would be highly unlikely. Future studies should focus on targeting the migratory potential of surviving cells.

Versatile N-Methylaminooxy-Functionalized Polypeptides for Preparation of Neoglycoconjugates.

The preparation and characterization of a new set of well-defined polypeptides containing N-methylaminooxy side-chain functionality is described. These functional groups enabled the direct coupling of polypeptides with a variety of unmodified reducing saccharides in water to give neoglycopolypeptides in high yields. The use of different polypeptide scaffolds resulted in neoglycoconjugates with tunable chain conformations, hydrophobicity, and charge. These new neoglycopolypeptides were also found to be stable in aqueous media at pH 7.4 and 37 °C for 1 week. The combination of straightforward synthesis using unmodified saccharides, high yields of saccharide conjugation, and conjugate stability makes these polypeptides attractive candidates for development of degradable glycoprotein mimics.

Conformation-Directed Formation of Self-Healing Diblock Copolypeptide Hydrogels via Polyion Complexation.

Synthetic diblock copolypeptides were designed to incorporate oppositely charged ionic segments that form ß-sheet-structured hydrogel assemblies via polyion complexation when mixed in aqueous media. The observed chain conformation directed assembly was found to be required for efficient hydrogel formation and provided distinct and useful properties to these hydrogels, including self-healing after deformation, microporous architecture, and stability against dilution in aqueous media. While many promising self-assembled materials have been prepared using disordered or liquid coacervate polyion complex (PIC) assemblies, the use of ordered chain conformations in PIC assemblies to direct formation of new supramolecular morphologies is unprecedented. The promising attributes and unique features of the ß-sheet-structured PIC hydrogels described here highlight the potential of harnessing conformational order derived from PIC assembly to create new supramolecular materials.