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.

Recent advances of nanotechnology-based tumor vessel-targeting strategies

“…NO is an endogenous platelet inhibitor, which can inhibit various functions of platelets. Xu [ 86 ] used albumin as a carrier, surface modified NO donor (S-nitrosothiols, SNO), and loaded with chemotherapeutic drug PTX, to prepare an ultrasonic-responsive nanosystem. Under the action of ultrasound, the nanosystem could release NO, which can break the tumor vascular barrier and promote the accumulation of PTX and infiltration of T cells.…”

Stimuli Responsive Nitric Oxide-Based Nanomedicine for Synergistic Therapy

“…The breaking of bonds NO therapy-MRI [88] TPZ/HMTNPs-SNO R-SNO The breaking of bonds NO therapy-SDT-USI [89] IMesNO/DOX@MCs IMesNO The breaking of bonds NO therapy-chemotherapy [90] GSNO/Ce6@ZIF-8@Cytomembrane (GCZ@M) GSNO Oxidation-reduction reaction NO therapy-SDT [91] SNO-HSA-PTX R-SNO The breaking of bonds NO therapy-chemotherapyimmunotherapy [92] peptide−HMSN−LA L-Arg Oxidation-reduction reaction NO therapy-SDT [93] X-ray PEG-USMSs-SNO R-SNO The breaking of bonds NO therapy-radiotherapy [94] Bi-SNO R-SNO The breaking of bonds NO therapy-radiotherapy-CT imaging-PTT [95] ZGO:Mn-RBS RBS The breaking of bonds NO therapy-radiotherapy [96] GSH p(Gd-Az-JSK) alkynyl-JSK The nucleophilic attacking NO therapy-chemotherapy [97] PEG-b-NO-Dex-DOX NO-Dex Oxidation-reduction reaction NO therapy-chemotherapy [98] HCPT/CTS-NO-DMMA PSF Oxidation-reduction reaction NO therapy [99] α-CD-DOX-NO-DA R-SNO / NO therapy-chemotherapy [100] TNO3-DOX TNO3 Oxidation-reduction reaction NO therapy-chemotherapy [101] pH hollow microsphere (HM) DETA NONOate Hydrolysis reaction NO therapy-chemotherapy [49] GSNO-MNPs GSNO Hydrolysis reaction-oxidation-reduction reaction NO therapy-chemotherapy [102] NO-NCPs DETA NONOate Hydrolysis reaction NO therapy-PDT-PA imaging [103] Glucose L-Arg-HMON-GOx L-Arg Oxidation-reduction reaction NO therapy-starving therapy-USI [104] BPNs-Arg-GOx@MnO 2 (BAGM) L-Arg Oxidation-reduction reaction NO therapy-starving therapy-PTT [105] Abbreviations-BNN6: N,N -di-sec-butyl-N,N -dinitroso- conditions, but they are also not very stable under physiological conditions, leading to nonnegligible premature leakage; RSNOs are relatively stable under physiological conditions while chemical bonds' breakage and NO release can be achieved under hyperthermia [67].…”

“…Therefore, the function of tumor-associated platelets was inhibited, which induces the opening of the tumor vascular barrier and promotes the accumulation of PTX and immune cell invasion. Through the combination of chemotherapy, immunotherapy and NO gas therapy, remarkable tumor suppression was finally achieved with negligible side effects [92].…”

Ultrasound-Triggered Piezocatalysis for Selectively Controlled NO Gas and Chemodrug Release to Enhance Drug Penetration in Pancreatic Cancer

“…So far, some US-responsive NO delivery systems have been reported for biomedical applications, including NO microbubbles, , NO nanodroplets, nanoparticles modified with NO donors, ,, and nanomedicine encapsulating NO donors, in which NO gas molecules were either directly encapsulated for release upon US or loaded in the form of precursor for generating NO upon US. However, the way of physical packaging inevitably faces the risk of the premature drug leakage, not to mention some NO donors and their byproducts are not safe because of their toxic functional groups. , l -Arginine, as an endogenous NO donor with high biocompatibility, can be converted into NO and l -citrulline by the NO synthases (NOSs) in the physiological environment .…”