Nano Self-Assembly of Recombinant Human Gelatin Conjugated with α-Tocopheryl Succinate for Hsp90 Inhibitor, 17-AAG, Delivery

Abstract

A wide variety of drug delivery systems have been developed for the delivery of anticancer agents. One of the most frequently used natural biomaterials in drug delivery systems is polysaccharides; however, they are difficult to digest and to eliminate from the body after systemic administration due to their high molecular weight natures and the absence of degrading enzymes. Therefore, the development of degradable and eliminable natural biomaterials is critical for successful in vivo applications. In the present study, we report the development of self-assembled biodegradable nanoparticles based on recombinant human gelatin (rHG) modified with alpha-tocopheryl succinate (TOS). The rHG-TOS nanoparticles efficiently encapsulated 17-AAG (17-allylamino-17-demethoxygeldanamycin), a small molecular anticancer drug targeting heat shock protein 90. The formation of 17-AAG-loaded nanoparticles was confirmed using TEM and dynamic light scattering analysis and found to be within the size of 90-220 nm. The loading efficiency, sustained release pattern, and stability of 17-AAG from the rHG-TOS nanoparticles were determined using HPLC. Furthermore, the passive targeting of rHG-TOS nanoparticles to the tumor area via enhanced permeability and retention effect was examined by noninvasive live animal imaging in a tumor mouse model. Finally, the 17-AAG-loaded nanoparticles were nonimmunogenic and more efficient than free 17-AAG in manifesting an anticancer effect in the tumor model. Overall, our data demonstrate rHG-TOS as a promising tool for the delivery of 17-AAG featuring therapeutic efficacy and biocompatibility.

Recent advances in the use of gelatin in biomedical research

“…The tumour volume in mice treated with free 17-AAG was increased 20 times relative to the initial volume, whereas that of 17-AAG/ rHG-TOS nanoparticles was elevated 15 times (Won et al 2011). After intraperitoneal injection of DOXloaded GA-cross-linked GNPs into rats, the efficiency of DOX was enhanced compared to free drugs; however, high cardiotoxicity was also observed upon repeated administration.…”

“…Meanwhile, like other animal-origin proteins, gelatin is also questioned for its risk of carrying harmful agents such as transmissible spongiform encephalopathies (TSEs). However, in the case of gelatin, the rigorous manufacturing processes such as acid, alkaline and heat treatments should be sufficient effective to inactivate TSE (Won et al 2011). Additionally, recombinant human gelatin (rHG), which is commercially available, non-toxic and low immunogenic, can be an ideal substitute for the natural one (Won et al 2011).…”

Targeted cancer theranostics using alpha-tocopheryl succinate-conjugated multifunctional dendrimer-entrapped gold nanoparticles

“…Alpha-tocopheryl succinate (a-TOS) is known as a kind of vitamin E derivative that can induce apoptosis of various types of cancer cells, inhibit cells cycle, and disrupt the necessary autocrine signaling pathways of tumor growth [41,42]. a-TOS, composed of three domains (the functional domain, the signaling domain, and the hydrophobic domain) [43e45] can kill cancer cells, while not affecting the proliferation of most normal cells [46,47].…”

Low-Molecular-Weight Methylcellulose-Based Thermo-reversible Gel/Pluronic Micelle Combination System for Local and Sustained Docetaxel Delivery

“…3b). These results suggest that the renal route and glomerular filtration can gradually eliminate the MC gel (34).…”