Supramolecular Nitric Oxide Depot for Hypoxic Tumor Vessel Normalization and Radiosensitization

Abstract

In cancer radiotherapy, the lack of fixed DNA damage by oxygen in hypoxic microenvironment of solid tumors often leads to severe radioresistance. Nitric oxide (NO) is a potent radiosensitizer that acts in two ways. It can directly react with the radical DNA thus fixing the damage. It also normalizes the abnormal tumor vessels, thereby increasing blood perfusion and oxygen supply. To achieve these functions, the dosage and duration of NO treatment need to be carefully controlled, otherwise it will lead to the exact opposite outcomes. However, a delivery method that fulfills both requirements is still lacking. A NO depot is designed for the control of NO releasing both over quantity and duration for hypoxic tumor vessel normalization and radiosensitization. In B16‐tumor‐bearing mice, the depot can provide low dosage NO continuously and release large amount of NO immediately before irradiation for a short period of time. These two modes of treatment work in synergy to reverse the radioresistance of B16 tumors more efficiently than releasing at single dosage.

Drug Delivery Systems for Localized Cancer Combination Therapy

“…Various strategies in drug delivery and formulation have been used to enhance the efficacy of synergistic drug combinations for the treatment of cancer–many of which employ polymer chemistry, biomaterial science, and nanoformulations for achieving optimum drug delivery. − Of these approaches, polymeric nanoparticles are often formulated to coencapsulate and deliver therapeutic cargo for sustained delivery . For example, Houdaihed et al developed paclitaxel and everolimus-loaded polymeric nanoparticles grafted with PEGylated PLGA which increased systemic exposure and reduced neurotoxicity of the combination treatment in a breast cancer mouse model .…”

Cuprous Oxide-Based Dual Catalytic Nanostructures for Tumor Vascular Normalization-Enhanced Chemodynamic Therapy

“…Several studies reported that proper perfusion could efficiently alleviate hypoxia at the tumor site. 19 Thus, we explored the tumor oxygenation level after treatment with the different groups using the hypoxia-inducible factor (HIF-1α). As shown in Figure 5C, the Cu 2 O@Dex group showed that the HIF-1α level (green fluorescence) was significantly decreased compared with that in the PBS-treated group, and the semiquantitative analysis of fluorescence images in Figure 5D revealed that the hypoxia-positive area of the Cu 2 O@Dex group was 15.71%, while that of the PBS group was 63.67%, which implied that Cu 2 O@Dex could efficiently alleviate hypoxia by enhancing blood perfusion.…”

“…According to the previous studies, NO, as an active gas molecule, can dilate vessels, increase blood perfusion, and promote endothelial cell coverage by pericytes for improving the structure of tumor vessels. 18,19,33 The tumor perfusion and the percentage of endothelial cell coverage by pericytes increase when the tumor vessels are normalized by NO. Therefore, we first studied if Cu 2 O@Dex could catalyze the GSNO generating NO through the 4-amino-5-methylamino-2′,7′-difluorescein-diacetate (DAF-FM DA) probe.…”

“…Nowadays, the conventional strategies of vascular normalization mainly apply antiangiogenic drugs, − while the narrow normalization window and high treatment cost limit their further utilizations. , Nitric oxide (NO) has been revealed to dilate vessels, increase blood flow, and promote blood vessel maturation. ,, Chen et al reported the development of exogenous NanoNO to deliver NO into hepatocellular carcinoma for vascular normalization . Although the delivery of the exogenous donor appears to achieve a satisfactory vascular normalization effect, weaknesses including unexpected decomposition and insufficient loading are inevitable.…”

A Tetramethylpyrazine Releasing Hydrogel can Potentiate CAR-T Cell Therapy against Triple negative breast cancer by Reprogramming Tumor Vasculatures

“…In addition, increased intratumoral levels of nitrogen oxide (NO) and vascular endothelial growth factor (VEGF) through distinct mechanisms could effectively remodel tumor vasculature due to their potency in dilating blood vessels and in regulating angiogenesis, respectively [19,[25][26][27]. Tetramethylpyrazine (TMP), an alkylpyrazine isolated from traditional Chinese medicine, Ligusticum wallichii (Chuan Xiong), has been used for the treatment of varying vascular diseases in China for ~40 years, probably ascribing to its potency in promoting VEGF expression and NO production in vascular endothelial cells [28].…”