Multifunctional PLGA-based Nanocomposites For Imaging-guided Combination Cancer Therapy

In recent years,the development of nanotechnology has had a tremendous impact on the fabrication of versatile nanocarriers,providing opportunities for the drug delivery and combination cancer therapy.And a variety of organic or inorganic materials have been used to prepare drug-loaded nanocarriers for achieving safe and improved antitumor efficacy.With the development of various imaging techniques and therapeutic methods,nanocarriers that integrated imaging and therapeutic agents have shown great potential for imaging-guided cancer treatment.Nanocarriers fabricated based on poly?D,L-lactic-co-glycolic acid,PLGA?can be degraded into natural non-toxic lactic acid and glycolic acid in the body,and eventually decomposed into water and carbon dioxide,which showed excellent biocompatibility and biodegradability.Therefore,based on the excellent properties of PLGA nanoparticles as drug delivery vehicles,we have had integrated imaging and therapeutic agents into PLGA nanoparticles.Surface modification of PLGA nanoparticles can further improve their biocompatibility or endow them with the targeted ability.Our present work mainly evaluated the potential of the developed multifunctional PLGA nanocarriers as effective theranostic agents for tumor imaging and therapy.In chapter two,we developed a nanocomposite for co-delivery of drug and gene.Firstly,we used double emulsion method to prepare the quantum dots?CdSe/ZnS QDs?,Fe₃O₄ nanoparticles,and antitumor drug doxorubicin?DOX?co-encapsulated PLGA nanoparticles,followed by the surface modification of PEI-PEG-FA?PPF?and adsorption of VEGF shRNA that against vascular endothelial growth factor?VEGF?.The data showed that the DOX-loaded luminescent/magnetic PLGA nanocomposites?denoted as LDM-PLGA/PPF/VEGF shRNA?can enter tumor cells via folate receptor-mediated targeted effects,and then provide effective chemo-gene combination therapy of cancer after the drug release,lysosomal escape,gene expression,and drug diffusion into the nucleus.The data also validated that LDM-PLGA/PPF/VEGF shRNA can simultaneously deliver DOX and VEGF shRNA into tumor cells and effectively downregulate the expression of VEGF,showing excellent antitumor effects.The maging data proved that LDM-PLGA/PPF/VEGF shRNA can be utilized as an efficient contrast agent for enhanced T₂-weighted magnetic resonance imaging and fluorescence imaging of tumors.In chapter three,we fabricated the hybrid PLGA nanoplatform that simultaneously delivered the chemotherapeutic drugs?DOX?and near-infrared light absorbing agents?ICG?with bovine serum albumin?BSA?modification.The obtained bovine serum albumin?BSA?modified PLGA nanoparticles?IDPNs?exhibited good stability and biocompatibility.BSA modification can not only improve the biocompatibility of the nanoparticles,but also enhance the stability of polymer nanoparticles.As one kind of near-infrared light absorbing agents,indocyanine green?ICG?can not only be used as a photothermal agent for photothermal therapy of tumors,but also used as the imaging agent for tumor fluorescence and photoacoustic imaging.In vitro experiments have demonstrated that IDPNs showed good stability,biocompatibility,photothermal efficacy,fluorescence/photoacoustic imaging capabilities and near-infrared light-triggered drug release behavior.Cellular experiments demonstrated that endocytosis of IDPNs is carried out by the clathrin-mediated endocytic pathway,and the near-infrared laser irradiation can trigger the durg release and facilitate the escape of released DOX from lysosomes to cytoplasm,and then enter the nucleus to exert cytotoxicity.And the chemo-photothermal therapy provided by the IDPNs under near-infrared laser irradiation exhibited an enhanced antitumor effect,which is superior to any single treatments?chemotherapy or photothemal therapy?.The study in chapter four is based on the research work in chapter three,the in vivo fluorescence/photoacoustic imaging capabilities,tumor tissue targeting effects,antitumor effects,and intratumoral distribution of IDPNs were further evaluated.The results demonstrated that IDPNs can be efficiently accumulated into tumor tissues through passive targeting,and realize fluorescence/photoacoustic imaging of tumors with high sensitivity and high spatial resolution.IDPNs with exposure to near-infrared laser irradiation after intravenous injection could effectively suppress the tumor growth in EMT-6 tumor-bearing mice through the combined chem-photothermal therapy without causing systemic toxicity,resulting in the almost elimination of tumor tissues,the therapeutic effect of which was much better than any single treatment?chemotherapy or photothemal therapy?.Furthermore,laser irradiation treatment could promote the penetration of drug molecules into the deep tumor tissues.The in vivo data proved that IDPNs can be used as an effective theranostic agents for dual-modality imaging-guided combined cancer therapy.