Tumor Micro-Environment Responsive Nano-Pomegranates For Sensitisizing Cancer Radiotherapy

Nanomedicine has many advantages in the treatment of tumors and other diseases,which can better enrich the lesion site and effectively avoid toxic and side effects.In order to further improve the effect of nanomedicine in the treatment of biological diseases,we need to adjust many properties of nanomedicine.For example:size,surface charge,and surface hydrophilicity/hydrophobicity.By rationally designing these characteristics of nanomedicines,nanomedicines can be more efficiently used in vivo and reduce toxic and side effects.Clinically,radiotherapy and chemotherapy are still the most important treatment methods.How to improve the therapeutic effect of radiotherapy and chemotherapy through nanomaterials is still facing challenges.Nanosensitizers have been one of the most important researchs and applications for radiotherapy.However,after administering systemically before reaching the nucleus of tumor cells that are resistant to radiotherapy,nanosensitizers face multiple physiological barriers formed by the blood,tumor microenvironment,nuclear membrane.Therefore,its critically important to rationally optimize the size and surface characteristics of nano-sensitizers for efficiently crossing a variety of physiological barriers in the body and reaching the location of tolerant tumor reagion to sensitize radiotherapy.This thesis focuses on the design of nano-sensitizer systems based on gold nanoparticles with a variety of nano-properties.These two nano-sensitiziers also have the property of reporting therapeutic effects and alleviating tumor hypoxia.Focus on the problems of delivery of therapeutic reagents,report of treatment effects during tumor treatment and the effects of surface hydrophilicity/hydrophobicity on in vivo behavior;the research direction of this thesis is mainly divided into three parts:1.The efficacy of nano-radiosensitizers in cancer therapy has been primarily impeded by their limited accessibility to radioresistant cancer cells residing deep inside tumor tissues.The failure to report tumor response to radiotherapy generally delays adjustment of the treatment schedule and sets up another substantial obstacle to clinical success.Here,we develop a nano-pomegranate(RNP)platform that not only visualizes the cancer radiosensitivities but also potentiates deep tissue cancer radiotherapy via elevated passive diffusion and active transcytosis.The RNPs are engineered through the programmed self-assembly of a tumor environment-targeting polymeric matrix and modular building blocks of ultrasmall gold nanoparticles(Au5).Once RNPs reach the tumors,the environmental acidity triggers the splitting and surface cationization of Au5.The small dimension of Au5 allows its passive diffusion while positive surface charge enables its active transcytosis to cross the tumor interstitium.Meanwhile,the reporter element monitors the feedback of favorable radiotherapy responsiveness by detecting the activated apoptosis after radiation.The pivotal role of RNPs in improving and identifying radiotherapeutic outcomes is demonstrated in various tumor bearing mouse models with different radiosensitivities.In summary,our strategy offers a promising paradigm for deep tissue drug delivery as well as individualized precision radiotherapy.2.Abundant extracellular matrix(ECM),high interstitial pressure,and vascular dysfunction feature the development of pancreatic tumors,which present substantial barriers for penetration of therapeutic agents and blood perfusion.The restriction of blood perfusion limits the oxygen delivery to avascular region and causes hypoxia in deep tumor tissue.The scarcity of oxygen in tumor hypoxic region further limits the clinical applications of radiotherapy(RT).Here,we develop an ECM tampering size-transformable nano-pomegranate conjugating with collagenase-1(TNPC)to ablate ECM and normalize vascular system.The decomposition of ECM effectively decreases hypoxia and concurrently improves the diffusion and accumulation of radiosensitizers through tumor tissue,which significantly sensitizes the pancreatic cancer to radiotherapy.The TNPC orchestrated with-5 nm gold nanoparticles(Au5),pH responsive polymer and ECM targeted collagenase-1(col-1).The TNPC maintained a large size(～130 nm)during blood circulation whereas it dramatically dissociated into Au5 and released col-1 immediately when it suffered from acidic tumor microenvironment.The released col-1 effectively decomposes the predominating constituent of ECM,stromal collagen,re-expanding the blood vessels and increasing blood flow and followed with conspicuous amelioration of anaerobic tumor microenvironment.Simultaneously,Au5 penetrate deeply and diffuse effectively into avascular region of pancreatic tumor.Upon X-ray irradiation,excessive Aus and enrichment of oxygen intensify radical species generation in deep region of tumor,sensitizing BxPC-3 pancreatic tumor featured dense desmoplastic stromal to radiotherapy(RT).Our work presents a new strategy to remodel the tumor microenvironment and relieve radioresistance of pancreatic cancer to radiotherapy.3.The surface hydrophilicity of nanoparticles is critically vital to their biological fates,including ultimate antitumor efficacy.Ascertaining the correlation between nanoparticles surface hydrophilicity and their biological behaviors is particularly important to optimize their antitumor efficacy.Herein,we designed a series of polymeric nanoparticles based on polyphosphates(PPs)with tunable surface hydrophilicity in molecular level.The results demonstrated that high surface hydrophilicity preferred lower protein absorption,better stability,longer blood circulation as well as more tumor accumulation but lower cellular entry.After applying the drug-loaded PPylated nanoparticles for cancer treatment,we found that consistent with the treatment outcomes of the nanoparticles with high surface hydrophilicity,the poor surface hydrophilic nanoparticles showed excellent anti-tumor therapeutic effect in both primary and metastatic tumor.Further analyses revealed that the similar antitumor efficacies were achieved due to the overlapped balance of tumor accumulation and cellular uptake,demonstrating the particular importance of nanoparticles surface hydrophilicity regulation on antitumor efficacy.Our work provides a potent guideline for rational designation of surface hydrophilicity on nanoparticles to optimize cancer treatment.