Development of Polymeric-Drug Conjugates for Delivering the HSP90 Inhibitor SNX5422

Heat shock protein 90 (HSP90) inhibition has been considered as a potential treatment option for prostate cancer. However, several HSP90 inhibitors including SNX5422 were removed from cancer clinical trials due to visual toxicities. Recent animal studies showed retinal damage produced by HSP90 inhibitors and suggested a relationship between the plasma/eye ratio of the inhibitor and the retinal damage produced. The blood ocular barrier is known to be an obstacle for large molecules like polymers. Therefore, a polymer-HSP90 inhibitor conjugate could restrict the access to the eye of the inhibitor achieving a higher plasma/eye ratio than the free HSP90 inhibitor. The purpose of this study was to develop a PEG-SNX5422 conjugate through a dendritic structure (EDTA) to allow the incorporation up to 3 SNX5422 molecules per PEG chain. The system includes Cathepsin B degradable linkers for enzymatically triggered release of the drug. We synthesized several PEG-SNX5422 conjugates with different PEG lengths (5k to 20k) and different number of SNX5422 molecules attached to the polymer chain. The conjugates where submitted to an optimization process testing their in vitro characteristics: all the conjugates were stable in different buffers, including serum proteins, and able to release SNX5422 in the presence of the enzyme Cathepsin B. We observed a relationship between water solubility and growth inhibition properties of the conjugates against 2 different prostate cancer cell lines. PEG20k conjugates had the highest stability, water solubility and cytotoxic activity against prostate cancer cells, therefore it was selected for in vivo testing using a mouse model. PEG20k-SNX3 conjugates showed a significantly higher plasma/eye ratio than the free drug, suggesting that these conjugates can modify the biodistribution of SNX5422 and reduce its visual toxicities.