Delivery of HSP90 Inhibitor Using Water Soluble Polymeric Conjugates with High Drug Payload.

Abstract:

PURPOSE:HSP90 (Heat shock protein 90kD) has been validated as a therapeutic target in Castrate Resistant Prostate Cancer. Unfortunately, HSP90 inhibitors suffer from dose-limiting toxicities that hinder their clinical applications. Previously developed polymeric delivery systems for HSP90 inhibitors had either low drug content or low biological activity suggesting the need for better delivery system for HSP90 inhibitors. METHODS:We developed a simplified synthetic strategy to prepare polyethylene glycol based water-soluble polymeric system for model HSP90 inhibitor geldanamycin (GDM). We then investigated the effect of cathepsin B degradable linker and drug content in polymeric conjugates on their growth inhibitory property using DU145 (androgen independent) and LNCaP (androgen dependent) cell lines. RESULTS:Water-soluble polymeric conjugates were synthesized with GDM content ranging from 9 to 30% wt/wt. We demonstrated the importance of cathepsin B degradable linker from the context of drug content and different prostate cancer cell lines. The most active conjugate against DU145 cells exhibited IC50 value of 2.9 μM. This was similar to the IC50 (2.1 μM) of small molecular drug aminohexane geldanamycin. CONCLUSION:Water-soluble polymeric conjugate with high drug content was synthesized that exhibited in-vitro growth inhibitory activity similar to small molecular weight HSP90 inhibitor. Graphical Abstract Water soluble degradable polymeric conjugate for the delivery of Geldanamycin.

journal_name

Pharm Res

journal_title

Pharmaceutical research

authors

Suárez Del Pino JA,Kolhatkar R

doi

10.1007/s11095-017-2249-5

subject

Has Abstract

pub_date

2017-12-01 00:00:00

pages

2735-2748

issue

12

eissn

0724-8741

issn

1573-904X

pii

10.1007/s11095-017-2249-5

journal_volume

34

pub_type

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