A Novel Vascular Disrupting Agents Noncovalent Polymeric Nanomedicine:Significantly Increased Antitumor Therapeutic Efficiency

This work was supported by the National Natural Science Foundation of China(Nos.52025035,52103195).The comprehensive graphic content and graphic abstract were created with BioRender.com by coauthors.

Transcatheter Arterial Embolization Combined with Anti-vascular Agent Combretastatin A4 Phosphate Inhibits Growth and Vascularization of Liver Tumor in an Animal Model

Objective This study aimed to investigate the effect of combretastatin A4 phosphate(CA4P)on proliferation,migration,and capillary tube formation of human umbilical vein endothelial cells(HUVECs)and the efficacy of transcatheter arterial embolization combined with CA4P in the treatment of rabbit VX2 liver tumor.Methods The effects of different concentrations of CA4P on proliferation,migration and capillary tube formation of HUVECs were investigated by cell proliferation assay,wound healing assay and capillary tube formation assay,respectively.Thirty-two rabbits implanted with liver VX2 tumors were randomly divided into 4 groups.After catheterization of the left hepatic artery,the infusion was performed using normal saline(group A),CA4P aqueous solution(group B),lipiodol and polyvinyl alcohol particles(group C),and CA4P lipiodol emulsion and polyvinyl alcohol particles(group D),respectively.Half of the animals in each group were euthanized for immunohistochemical analysis to evaluate microvessel density(MVD)at 3 days post-treatment.The other half were examined by MRI and histology to evaluate tumor growth and necrosis at 7 days post-treatment.Results CA4P could inhibit the proliferation,migration,and tube formation of HUVECs in cell experiments.After interventional treatment,the level of MVD in group D was lower than that in group C(P<0.01).The tumor volume in group C or D was lower than that in group A or B(P<0.01).The tumor necrosis rate was higher in group D than in the other groups.Conclusion The study suggests that CA4P could inhibit the proliferation,migration,and capillary tube formation of HUVECs,and transcatheter arterial embolization combined with CA4P could inhibit the growth of VX2 tumor and obviously induce tumor necrosis.

Vascular disrupting agent-induced amplification of tumor targeting and prodrug activation boosts anti-tumor efficacy

Vadimezan,one of the typical vascular disrupting agents(VDAs) currently in clinical trials,has been extensively implemented for cancer research,whereas its clinical efficacy is adversely affected by the inevitable side effects.Inspired by Vadimezaninduced intratumoral coagulation activation and hypoxia aggravation,we report a strategy by utilizing these biological effects to achieve targeted delivery and activation of hypoxia-activated prodrug(HAP) thus to maximize the therapeutic effect of Vadimezan.By encapsulating HAP tirapazamine into poly(lactic-co-glycolic acid)(PLGA) nanocarriers along with the modification of clot-binding peptide,the obtained nanoplatform could target tumors under the coagulation activation effect of Vadimezan.Meanwhile,the aggravated hypoxia tumor microenvironment induced by Vadimezan can also boost hypoxia-activated chemotherapy.In the murine tumor model,this strategy showed 80.0% suppression of tumor growth,indicating its great potential in tumor treatment.This study offers an ingenious tactic for the combination of vascular disrupting therapy and hypoxia-activated chemotherapy,which may open up a window of the VDAs-based combination therapy.

A Novel CA4P Polymeric Nanoparticle for Murine Hepatoma Therapy

Combretastatin A4 phosphate(CA4P)is a potent vascular disrupting agent with good water solubility.However,it is only effective at high doses,which decreases clinical applicability.Herein,we designed stable CA4P polymeric nanoparticles(CA4P NPs)consisting of various cholesterol derivatives,and with a drug loading efficacy of 93%.The nanoparticles released CA4P in a sustained manner and achieved a 72%inhibition rate in the murine H22 liver tumor model,which was about 2.9-fold higher than that of free CA4P(24.6%).Furthermore,the carrier components of CA4P NPs were metabolized to arginine,cholesterol,ethanol and poly(ethylene glycol)in vivo;therefore,the CA4P NPs are safe and have significant potential for clinical translation.

Artificial tumor microenvironment regulated by first hemorrhage for enhanced tumor targeting and then occlusion for synergistic bioactivation of hypoxia-sensitive platesomes

The unique characteristics of the tumor microenvironment(TME)could be exploited to develop antitumor nanomedicine strategies.However,in many cases,the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity.Given the amplified characteristics of TME regulated by vascular disrupting agents(VDAs),nanomedicines may achieve unexpected improved efficacy.Herein,we fabricate platelet membrane-fusogenic liposomes(PML/DP&PPa),namely“platesomes”,which actively load the hypoxia-activated pro-prodrug DMG-PR104A(DP)and physically encapsulate the photosensitizer pyropheophorbide a(PPa).Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate(CA4P),PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P.First,CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention(EPR)effect,and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa.Besides,CA4P-induced vascular occlusion inhibits oxygen supply,followed by photodynamic therapy-caused acute tumor hypoxia.This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis.Thus,such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation,and provides a preferable solution to high-efficiency cancer therapy.