Abstract
Herein we report synthesis, characterization and preclinical applications of a novel hybrid nanomaterial Toco-Photoxil developed using vitamin E modified gold coated poly (lactic-co-glycolic acid) nanoshells incorporating Pgp inhibitor d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as a highly inert and disintegrable photothermal therapy (PTT) agent. Toco-Photoxil is highly biocompatible, physiologically stable PTT material with an average diameter of 130 nm that shows good passive accumulation (2.3% ID) in solid tumors when delivered systemically. In comparison to its surface modified counterparts such as IR780-Toco-Photoxil, FA-Toco-Photoxil or FA-IR780-Toco-Photoxil accumulation are merely ~0.3% ID, ~0.025% ID and ~0.005% ID in folate receptor (FR) negative and positive tumor model. Further, Toco-Photoxil variants are prepared by tuning the material absorbance either at 750 nm (narrow) or 915 nm (broad) to study optimal therapeutic efficacy in terms of peak broadness and nanomaterial’s concentration. Our findings suggest that Toco-Photoxil tuned at 750 nm absorbance is more efficient (P = 0.0097) in preclinical setting. Toco-Photoxil shows complete passiveness in critical biocompatibility test and reasonable body clearance. High tumor specific accumulation from systemic circulation, strong photothermal conversion and a very safe material property in body physiology makes Toco-Photoxil a superior and powerful PTT agent, which may pave its way for fast track clinical trial in future.
Highlights
IntroductionThe non-biodegradable nature of silica-gold hybrid nanoshells poses great concern in terms of their elimination from the body while the low stability of LiposAu at physiological condition makes intra-tumoral delivery of the material as the only choice
PLGA nanoparticles were prepared by an emulsion-solvent evaporation method using antibacterial and antifungal agent d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS, an FDA-approved vitamin E modified emulsifier) (Fig. 1)
Hydrodynamic diameter determined by dynamic light scattering (DLS) was ~142.2 nm and size determined using scanning electron microscope (SEM) found to be ~100 nm (Fig. 2a and Supplementary Fig. S1a)
Summary
The non-biodegradable nature of silica-gold hybrid nanoshells poses great concern in terms of their elimination from the body while the low stability of LiposAu at physiological condition makes intra-tumoral delivery of the material as the only choice Due to these limitations, their potential as PTT agent in the cancer clinic is limited. Review of fundamental physiochemical properties (size, charge, stability, and surface modification) is critical as these factors immensely affect the nanomaterials biodistribution, transport across vascular walls as well as retention in tumor Keeping these viewpoints, in this study we have fabricated a disintegrable and highly inert TPGS incorporated PLGA nanoshells and tested its effectiveness as a stand-alone photothermal therapy agent in preclinical model. Inclusion of critical toxicity studies like hemolysis, reactive oxygen species (ROS) measurement, apoptosis alongside full spectrum biochemical assessments are some of the critical aspects presented here
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