More than 50% of all cancer patients receive radiation therapy. The clinical delivery of curative radiation dose is strictly restricted by the proximal healthy tissues. We propose a dual-targeting strategy using vessel-targeted-radio-sensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. The resulting tumor vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/nanoparticle toxicity, extending its utility to intransigent or nonresectable tumors that barely respond to standard therapies.
Graphical abstract
KeywordsGold nanoparticles; image-guided radiation therapy; endothelial radiation damage; tumor vascular disruption Nanoparticles for radiation therapy have been an active area of research for several decades in oncology. More than 50% of cancer patients receive therapeutic radiation at some stage of their treatment course. Although highly effective for inflicting cellular damage, the specificity of radiation therapy is mainly derived from the geometric restriction of radiation beams. Sparing of healthy tissues and organs from radiation can be particularly challenging when treating tumors that are located in deep-seated anatomical locations. A strategy to intensify the tumor damage without adding additional risk to the healthy tissue is extremely advantageous in the clinic.Multifunctional metallic nanoparticles have excellent potential as radiosensitizing agents primarily due to the superior interaction cross-section for high-z-elements when irradiated with low-energy X-rays. 1 This interaction results in the emission of short-range photoelectrons and Auger electrons, which can impose damage to the tumor cellular or subcellular structures. 2,3 Gold nanoparticles (AuNP) are of interest in radiation therapy due to its high k-edge (≈81 keV) and biocompatibility. In contrast to i.v. administered radioactive probes, gold is nontoxic in moderate quantities. [4][5][6] By specifically targeting AuNP to malignant tumor cells using "enhanced permeability and retention" (EPR) driven passive or peptide/antibody-mediated active tumor targeting, radiation damage can be invoked to the tumor cells upon irradiation. [7][8][9][10][11][12][13][14][15][16] Several preclinical studies have demonstrated this in different preclinical tumors, including prostate, breast, head and neck, cervical, sarcoma, glioblastoma, colorectal, and melanoma. 14,[17][18][19][20][21][22][23][24][25] Previous studies have examined the potential for a classic clonogenic effect in cancer cells leading to improved radiotherapeutic efficacy. To this end, EPR-mediated passive targeting has been used to attain high AuNP deposition in the tumor cells. Although there are several benefits attributed to passive tumor targeting, recent preclinical and clinical studies have shown that EPR-mediated passive tumor targeting was significantly less efficient (≈2-fold) in slow-growing animal pancreatic adenocarcinoma (PDAC) models versus fast...