Transferrin Modified GSH Sensitive Hyaluronic Acid Derivative Micelle to Deliver HSP90 Inhibitors to Enhance the Therapeutic Efficacy of Brain Cancers

SIMPLE SUMMARY: Heat shock protein 90 (HSP90) is a key element of a multi-chaperone complex involved in the stabilizing of many client proteins, oncoproteins, which play essential roles in tumorigenesis. As the result, HSP90 has been taken as a promising target for anticancer therapies. AUY922 has good antitumor activity by inhibiting the ATPase activity of HSP90, while it has certain limitations, including poor water solubility and lack of selectivity, which have incited the development of a novel targeted nanoformulation. In this study, we have successfully synthesized and characterized a GSH-sensitive micelle that can encapsulate hydrophobic AUY922 in its core region to enhance its therapeutic efficacy against brain cancers. All in vitro and in vivo experimental results showed nanoformulated AUY922 has a better therapeutic efficacy against brain cancer in comparison to the free AUY922. ABSTRACT: Herein, GSH-sensitive hyaluronic acid-poly(lactic-co-glycolic acid) (HA-SS-PLGA) was synthesized. Surface modification of PLGA with hyaluronic acid produced a highly stable micelle at physiological pH while a micelle was destabilized at a higher GSH level. Fluorescence microscopy results showed that rhodamine-encapsulated micelle was taken up by brain cancer cells, while competitive inhibition was observed in the presence of free HA and free transferrin. In vitro cytotoxicity results revealed that transferrin-targeted nanoformulated AUY922 (TF-NP-AUY922) shows higher cytotoxicity than either free AUY922 or non-targeted AUY922-loaded micelles (NP-AUY922). In comparison to the control groups, free AUY922, TF-NP-AUY922 or NP-AUY922 treatment revealed the upregulation of HSP70, while the expression of HSP90 client proteins was simultaneously depleted. In addition, the treatment group induced caspase-dependent PARP cleavage and the upregulation of p53 expression, which plays a key role in apoptosis of brain cancer cells. In vivo and ex vivo biodistribution studies showed that cypate-loaded micelle was taken up and accumulated in the tumor regions. Furthermore, in vivo therapeutic efficacy studies revealed that the AUY922-loaded micelle significantly suppressed tumor growth in comparison to the free AUY922, or control groups using tumor-bearing NOD-SCID mice. Moreover, biochemical index and histological analysis revealed synthesized micelle does not show any significant cytotoxicity to the selected major organs. Overall, a synthesized micelle is the best carrier for AUY922 to enhance the therapeutic efficiency of brain cancer.