Targeted Drug Delivery by Radiation-Induced Tumor Vascular Modulation

Abstract

Effective drug delivery is severely restricted by the presence of complex pathophysiological barriers in solid tumors. In human pancreatic adenocarcinoma, mature and hypopermeable tumor blood vessels limit the permeation and penetration of chemo or nanotherapeutics to cancer cells and substantially reduce the treatment efficacy. New, clinically-viable strategies are therefore sought to breach the neoplastic barriers that prevent optimal tumor-specific drug delivery. Here, we present an original idea to boost targeted drug delivery by selectively knocking down the tumor vascular barrier in a poorly permeable human pancreatic cancer model. For the first time, we demonstrate that clinical irradiation (10 Gy, 6 MV) can induce tumor vascular modulation when combined with tumor endothelial-targeting gold nanoparticles. Active disruption of tumor blood vessels by nanoparticle-combined radiotherapy led to increased vessel permeability and improved tumor uptake of two prototypical model nanodrugs: i) a shortcirculating nanocarrier with MR-sensitive gadolinium (Gad-NC; 8 kDa; t1/2=1.5 h) and ii) a longcirculating nanocarrier with fluorescence-sensitive NIR dye (FL-NC; 30 kDa; t1/2=25 h).Functional changes in the altered tumor vessel dynamics, measured by relative changes in permeability (Ktrans), flux rate (Kep) and extracellular interstitial volume (Ve) were consistent with the concomitant increase in nanodrug delivery. This combination of radiation-induced antivascular and nanodrug-mediated anti-tumor treatment offers high therapeutic benefit for tumors with pathophysiology that restricts efficient drug delivery.

Overcoming Vascular Barriers to Improve the Theranostic Outcomes of Nanomedicines

“…demonstrated that a single low dose of radiation (2 Gy) enhanced vascular bursting via a cascade of changes to the tumor vasculature, increasing cytotoxic T‐lymphocyte membrane‐coated nanodrug carrying paclitaxel delivery (Figure 16c–g). [ 105 ] It resulted in the significantly increased tumor therapy effect (tumor growth inhibition: ≈88.50%) than the only nanodrug‐treated group (tumor growth inhibition: 56.68%). In 2019, Berbeco and co‐workers used clinical radiation to activate the tumor endothelial‐targeted gold nanoparticles to selectively induce a tumor neovessel damage in a human pancreatic adenocarcinoma tumor model, which obviously increased tumor vascular permeability, causing more than twofold increase in nanodrug delivery (Figure 16h).…”

“…In 2019, Berbeco and co‐workers used clinical radiation to activate the tumor endothelial‐targeted gold nanoparticles to selectively induce a tumor neovessel damage in a human pancreatic adenocarcinoma tumor model, which obviously increased tumor vascular permeability, causing more than twofold increase in nanodrug delivery (Figure 16h). [ 105 ]…”

Nanomaterials: An overview with respect to biological applications

“…The nano size is one of the important features which make them capable to diffuse through various membranes. Permeability feature with the targeted delivery to the tumor site include the enhanced effect of retention are the important features of the nanoparticles [35][36][37][38]. 2D nanomaterials have the ability of best adsorption due to which they can easily adsorb the drug molecules for the drug delivery [29].…”

Translating nanomedicines: Thinking beyond materials? A young investigator's reply to ‘The Novelty Bubble’

“…Standardizing nanomaterial characterization and reproducibility of experimental results are also issues in the field which need to be addressed [24][25][26][27]. The gradual movement toward full open access, preprint servers like bioRxiv (biorxiv.org), and ongoing technological innovations increasingly provide opportunities to exchange experimental results [28]. For example, several journals have introduced the option to publish data (e.g.…”