Damaging Tumor Vessels with an Ultrasound-Triggered NO Release Nanosystem to Enhance Drug Accumulation and T Cells Infiltration.

Abstract

INTRODUCTION:

Limited by tumor vascular barriers, restricted intratumoural T cell infiltration and nanoparticles accumulation remain major bottlenecks for anticancer therapy. Platelets are now known to maintain tumor vascular integrity. Therefore, inhibition of tumor-associated platelets may be an effective method to increase T cell infiltration and drug accumulation at tumor sites. Herein, we designed an ultrasound-responsive nitric oxide (NO) release nanosystem, SNO-HSA-PTX, which can release NO in response to ultrasound (US) irradiation, thereby inhibiting platelet function and opening the tumor vascular barrier, promoting drug accumulation and T cell infiltration.

METHODS:

We evaluated the ability of SNO-HSA-PTX to release NO in response to US irradiation. We also tested the effect of SNO-HSA-PTX on platelet function. Plenty of studies including cytotoxicity, pharmacokinetics study, biodistribution, blood perfusion, T cell infiltration, in vivo antitumor efficacy and safety assessment were conducted to investigate the antitumor effect of SNO-HSA-PTX.

RESULTS:

SNO-HSA-PTX with US irradiation inhibited tumor-associated platelets activation and induced openings in the tumor vascular barriers, which promoted the accumulation of SNO-HSA-PTX nanoparticles to the tumor sites. Meanwhile, the damaged vascular barriers allowed oxygen-carrying hemoglobin to infiltrate tumor regions, alleviating hypoxia of the tumor microenvironment. In addition, the intratumoral T cell infiltration was augmented, together with chemotherapy and NO therapy, which greatly inhibited tumor growth.

DISCUSSION:

Our research designed a simple strategy to open the vascular barrier by inhibiting the tumor-associated platelets, which provide new ideas for anti-tumor treatment.

• Authors: Yan Xu, Jiwei Liu, Zhangya Liu, Guoguang Chen, Xueming Li, Hao Ren
• Journal: International journal of nanomedicine (Int J Nanomedicine) Vol. 16 Pg. 2597-2613 ( 2021) ISSN: 1178-2013 [Electronic] New Zealand
• PMID: 33833514 (Publication Type: Journal Article)
• Copyright: © 2021 Xu et al.

Chemical References

• Antineoplastic Agents, Phytogenic
• Nitroso Compounds
• S-nitrosoalbumin, human
• Nitric Oxide
• Paclitaxel
• Serum Albumin, Human

Topics

• Animals
• Antineoplastic Agents, Phytogenic (administration & dosage, pharmacokinetics, pharmacology)
• Apoptosis
• Breast Neoplasms (drug therapy, immunology, metabolism, pathology)
• Cell Proliferation
• Female
• Humans
• Lymphocytes, Tumor-Infiltrating (immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Nanoparticles (administration & dosage, chemistry)
• Nitric Oxide (metabolism)
• Nitroso Compounds (chemistry)
• Paclitaxel (administration & dosage, pharmacokinetics, pharmacology)
• Serum Albumin, Human (chemistry)
• Tissue Distribution
• Tumor Cells, Cultured
• Tumor Microenvironment (drug effects, immunology)
• Ultrasonic Waves
• Xenograft Model Antitumor Assays