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

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.

Nanomaterials for Drug Delivery and Cancer Therapy

“…These studies demonstrated the ability of liposomes in the delivery of DNA vaccines inoculated via the intranasal route to confer significant immune protection against respiratory infections in animal models. However, widespread adoption of liposome-based vaccines remains stunted by their relatively lower physical and chemical stability in aqueous dispersions during long-term storage [118]. Accordingly, numerous methods to improve the stability of liposome formulations during storage have been investigated, including freeze-drying, spray-drying, supercritical fluid technology, and lyophilization [119][120][121].…”

“…Conventional treatments have not been able to alleviate the consequences of this deadly disease. The development of targeted therapies for gastric cancer requires new technologies [118]. The most novel approach being considered is finding the primary targets, such as immune checkpoints such as PD-L1, in gastric cancer [119].…”

“…As a postformulation crosslinking strategy, LA residues were oxidized by Dithiothreitol (DTT) to ensure the selective vectorization of DTX to lung cancer both in vitro and in vivo as a consequence of SANPs destabilization within the tumor environment [115]. Moreover, HA-PLGA conjugates can be organized in redox-responsive nanoparticle structures by inserting GSH-responsive linkers between HA and PLGA counterparts [116], with the possibility to further enhance the site-specificity of the drug release by the insertion of other targeting elements such as FA [117] and Tf [118].…”

Antioxidants in brain tumors: current therapeutic significance and future prospects

“…Transferrin-targeted GSH-sensitive hyaluronic acid-poly(lacticco-glycolic acid) nanomicelle loaded with a heat shock protein 90 (Hsp90) inhibitor, AUY922 to enhance the therapeutic efficacy towards brain cancers. GSH conjugation allows fast release of AUY922 to the tumor site and cellular uptake through transferrin receptor [195].…”