Photodynamically Controllable Nanomedicine For Anticancer Therapy

Cancer is one of the main disease to harm human health.With the increasing incidence and mortality in recent years,we urgently need to develop a safe and effective treatment modality.Notably,nanomedincine has been widely developed and studied for cancer therapy because of its desired capabilities to increase drug solubility,improve drug stability,control drug release,prolong drug circulation,promote tumor accumulation,and reduce side effect.Doxil^??pegylated lipsomal doxorubicin?is the first nanomedicine approved by FDA to treat ovarian cancer,Kaposi's sarcoma,and multiple myeloma.Moreover,the first approval of polymeric nanomedicine,Genexol-PM^?,based on paclitaxel loaded PEG-PLA nanoparticles,has been used to treat ovarian cancer,lung cancer,and breast cancer,which inspired researchers to develop a series of nanomedicine into clinical trails including BIND-014,NC-6004.However,high drug loading,high cellular uptake efficiency,specific drug release in tumor,and low side effect represent a critical challenge for nanomedicine to achieve enhanced anticancer efficacy.In chapter 1,we present a brief literature overview on the current status,photodynamic therapy,tumor microenvironment responsive nanomedicine,and cascaded photo-chemo therapy.Efficient intracellular delivery of protein drugs and tumor-specific activation of protein functions are critical toward anti-cancer protein therapy.However,an omnipotent protein delivery system that can harmonize the complicated systemic barriers as well as spatiotemporally manipulate protein function is lacking.In chapter 2,we designed an“all-function-in-one”nanocarrier doped with photosensitizer?PS?and coupled with reactive oxygen species?ROS?-responsive,reversible protein engineering to realize cancer-targeted protein delivery and spatiotemporal manipulation of protein activities using long-wavelength visible light?635 nm?at low power density?5mW/cm²?.Particularly,RNase A was caged with H₂O₂-cleavable phenylboronic acid to form RNBC,which was encapsulated in acid-degradable,ketal-crosslinked PEI?KPEI?-based nanocomplexes?NCs?coated with PS-modified hyaluronic acid?HA?.Such NCs harmonized the critical processes for protein delivery.Tumor-specific light irradiation generated H₂O₂ to kill cancer cells and restore the protein activity,thus achieving synergistic anti-cancer efficacy.It is the first time to photo-manipulate protein functions by coupling ROS-cleavable protein caging with PS-mediated ROS generation,and the“all-function-in one”nanocarrier represents a promising example for the programmed anti-cancer protein delivery.The efficient encapsulation of drugs in nanoparticles,and the precise release of drug cargos in tumors represent a critical challenge for chemodrug delivery to achieve enhanced efficacy and reduced side effect.In chapter 3,we designed a combination strategy to sensitize the ROS-responsive prodrug delivery in tumors by photodynamic therapy?PDT?-induced ROS generation,and demonstrate the synergistic anti-cancer effect of PDT and PDT-triggered drug release through ROS-responsive mechanism.Particularly,H₂O₂-activatable prodrug?BE-CPT₂?was designed and co-delivered in one nanoparticle with haematoporphyrin as the photosensitizer?PS?using mPEG-PLA nanoparticles which possessed high drug loading and desired properties to overcome the multiple barriers.We demonstrated that the tumor site-specific PDT greatly enhanced the H₂O₂ level in tumor cells and efficiently triggered CPT release,affording effective and synergistic anti-cancer efficacy with low systemic toxicity.This study represents a novel and promising strategy to achieve cancer-specific therapeutic treatment through programmed combination of PDT-cascaded chemotherapy and PDT.The precise and selective delivery of chemodrugs into tumors represents a critical requirement for anti-cancer therapy.Intelligent delivery systems that are responsive to a single internal or external stimulus often lack sufficient cancer selectivity,which compromises the drug efficacy and induces undesired side effects.In chapter 4,we designed a cancer-targeting vehicle which allows highly cancer-selective drug release in response to cascaded external?light?and internal?hypoxia?dual triggers.Particularly,doxorubicin?DOX?-loaded,hypoxia-dissociable nanoparticles?NPs?were prepared from self-assembled polyethyleneimine-nitroimidazole?PEI-NI?micelles that were further co-assembled with hyaluronic acid-Ce6?HC?.Upon accumulation in tumor cells,tumor site-specific light irradiation?660 nm,10 mW/cm²?generated high levels of reactive oxygen species?ROS?and greatly enhanced the hypoxic levels to induce NPs dissociation and accordingly DOX release.Synergistic anti-cancer efficacy between DOX-mediated chemotherapy and Ce6-mediated photodynamic therapy?PDT?was thus achieved,resulting in reduced side effects to normal tissues/cells.Photodynamic therapy?PDT?eradicates cancer cells by converting intratumoral oxygen into reactive singlet oxygen?¹O₂?using photosensitizer and light.However,oxygen consumption during PDT can result in serious hypoxic condition and elevated hypoxia-inducible-factor-1??HIF-1??level that hamper further photodynamic efficacy and induce tumor metastasis.In chapter 5,we designed and developed a light-programmable,self-rectifiable,high drug loading NPs to co-encapsulate both photosensitizer?Ce6?and hypoxia-activatable camptothecin?CPT?prodrug?hQ-CPT₂?for synergistic anticancer treatment.PDT consumes oxygen upon light irradiation and further generates a hypoxic stress intracellularly,facilitating the drug?CPT?release from hypoxia-responsive hQ-CPT₂ NPs,which achieved tumor killing,inhibited HIF-1?activity to further enhance the therapeutic effect of PDT and prevent tumor metastasis.In addition,in vivo studies revealed that the Ce6 and hQ-CPT₂ co-loaded?hQ-CPT₂@Ce6?NPs afforded synergistic anti-cancer efficacy with minimal toxicity.This study provides a novel strategy to achieve the cancer-specific efficacy by utilize a negative facet of the PDT through elegant combination design.Finally,chapter 6 overviews the whole thesis and gives a future perspective in this field.