Construction Of Plasma Membrane-based Laser-controllable Drug Delivery Systems And Their Anticancer Applications

Cancer has become one of the leading threats to human health worldwide.Commonly used therapeutic strategies in clinical settings mainly include surgery,radiotherapy,and chemotherapy.Among them,chemotherapy has been proven to be effective for treating various types of cancers and metastatic tumors,and is thus recognized one of the most important therapeutic modalities.Unfortunately,chemotherapeutics are frequently criticized for their rapid body clearance,lack of tumor selectivity,and high systemic toxicity,leading to suboptimal therapeutic effectiveness and severe side effects.In this context,developing tumor-targeting and controllable drug delivery systems is of great importance to overcome the above limitations.In this thesis,we develop two types of light-controllable drug carriers based on intact red blood cells(RBCs).These drug carriers are constructed by modifying RBC surfaces with photosensitizers and loading therapeutic agents inside the RBCs.In such a design,the photosensitizers can efficiently disrupt RBC membranes upon laser irradiation and thus trigger a burst release of the loaded drugs.First,we systematically investigate how the use of different photosensitizers and surface modification strategies(physical absorption and covalent conjugation)influences the properties of the prepared drug carriers.We conclude that the covalent strategy ensures better modification stability and efficiency than those of its physical counterpart.In addition,2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-?(HPPH)and cypate are selected as two optimal photosensitizers for RBC modification as well as laser-triggered drug release.On the basis of the above conclusions,we next construct two drug delivery systems and evaluate their therapeutic efficacies for cancer treatments.For the first system,we load thrombin,a blood clotting-inducing enzyme,and tirapazamine(TPZ),a hypoxia-responsive chemodrug,into HPPH-modified RBCs.The as-engineered RBCs(termed Th/TPZ@HRBCs)maintain the same morphology and membrane protein components as natural RBCs,ensuring their ultralong retention time in blood circulation.When the tumor regions receive a laser irradiation treatment,a burst release of thrombin and TPZ from Th/TPZ@HRBCs can be rapidly triggered.In this scenario,the thrombin induces tumor vessel blockage and exacerbates tumor hypoxia,which further activates TPZ to form TPZ radical to exert a cytotoxic effect on tumor cells.In the other system,we fabricate a cypate-modified RBC carrier and load it with pirfenidon(PFD),an clinically used anti-fibrotic drug,and albumin-doxorubicin nanocomplexes(termed DOX@HSA).The as-formed HDPM@CRBCs show highly selective tumor accumulation under the guidance of a magnetic field,and upon laser irradiation,efficiently release the two encapsulated drugs.In vivo results demonstrate that the PFD inhibits the formation of extracellular matrix in tumor tissues,which significantly increases the penetration depth of DOX@HSA and therefore enhances the final anticancer efficacy.Apart from RBC-based carriers,we also develop a photosensitizing liposome as a plasma membrane-responsive platform for laser-controlled delivery of chemodrugs.In this example,we report that simply doping a hydrophobic photosensitizer protoporphyrin IX(Pp IX)into the lipid bilayer of a doxorubicin(Dox)-loaded liposome is a feasible way to promote the nuclear delivery of Dox.This facile strategy relies on the high affinity of Pp IX for the plasma membrane,which drives the doped Pp IX molecules to detach from the liposomes when encountering cancer cells.We demonstrate that this process can trigger the efficient release of the loaded Dox molecules before being trapped by lysosomes and allow them to enter the nuclei of cancer cells.Regarding the drug-resistant MCF-7/ADR cells,the overexpressed efflux pumps in the plasma membranes expel the internalized Dox.However,we strikingly find that the robust drug resistance can be reversed upon mild laser irradiation because the photodynamic effect of Pp IX disrupts the drug efflux system(e.g.,P-glycoprotein)and facilitates the nuclear entry of Dox.In addition,we demonstrate that this Pp IX doping strategy is also applicable for enhancing the effectiveness of cisplatin-loaded liposomes against both A549 and A549/DDP lung cancer cells.To summarize,in this thesis,we employ plasma membrane-based phototherapy as a modulation strategy for precise drug delivery and cancer therapy.On the one hand,photodynamic therapy is exploited as a trigger so that the RBC-based therapeutics are able to release their payloads in a spatiotemporally controllable manner.On the other hand,the plasma membrane-localized photodynamic therapy is found to modulate the membrane permeability and even reverse the multidrug resistance of cancer cells.Taken together,these studies provide a series of advanced therapeutic strategies for constructing light-responsive anticancer drugs and will benefit the development of precise drug delivery systems.