Design Of UCNPs-based Theraonostic Nanosystems And Their Targeted Applications In Pancreatic Cancer Therapy

Cancer stem cells?CSCs?,only a small proportion of cells in the cancer tissues,are suggested to be responsible for relapse,metastasis and prognosis of cancers partly due to their ability to self-renew themselves and differentiate into heterogeneous lineages of cancer cells.Surgical procedures,radiotherapy and chemotherapy are the main strategies in cancer therapies.While surgical resection can be potentially curative,many patients are not candidates for operative intervention due to widespread metastases.Moreover,other forms of therapies,such as radiotherapy and chemotherapy,have had limited effects,thereby emphasizing the need for the development of other forms of therapy.Photodynamic therapy?PDT?,as one kind of emerging modalities in cancer therapy,which has various advantages,such as negligible damage to adjacent tissues,low chemo-resistance,low recurrence,economics and convenience.PDT includes three key components,light resource,photosensitizers?PSs?and oxygen?O₂?.Upon excitation of the PS under lights with proper wavelengths,the PS is able to transfer the absorbed photon energy to the oxygen molecules in the surroundings,thereby generating cytotoxic singlet oxygen?¹O₂?to kill cancer cells.PDT can provide high specificity for the treatment of particular lesions through the control of light exposure to the photosensitizer,thereby minimizing any potential detrimental side effects on normal tissues.However,one major limitation with current PDT is its relatively low tissue penetration depth since most photosensitizers are excited by visible or even UV light,thus limiting its applications.And most PSs play the only role of photosensitization during the therapy,and more drugs are needed to realize multimodal synergetic therapy.Fortunately,mitoxantrone?MX?as one synthetic anthracenedione that was prepared in an attempt to produce an antitumor agent with less normal tissue toxicity than anthracycline antibiotics while retaining antitumor activity.Notably,MX has two major absorption peaks at 610 and 660 nm,which are wavelengths with relatively high transmission through the skin.Moreover,lanthanide-doped upconversion nanoparticles?UCNPs?allow for dual-modality magnetic resonance/upconversion luminescence?MR/UCL?imaging,and the visible light from UCNPs can trigger MX to reduce ¹O₂ under 980 nm excitation.However,the accumulation of theranostic nanosystems in the cancer tissues are rather limited only be the enhanced permeability and retention?EPR?effect.Functionalization of nanomedicine endow active targeting ability to cancer cells,which may result in better therapeutic efficacy.The epithelial cell adhesion molecule?EpCAM?has been considered a critical biomarker for cancer stem cells,and accounts for the proliferation,differentiation,migration,as well as invasion of cancer,thus becoming a promising target for designing theranostic nanosystems.Epithelial cell adhesion molecule?EpCAM?,overexpressed on the CSCs of many tumors including pancreatic cancer,which is associated with cancer progression and metastasis.Considering the above points,we creatively developed unique EpCAM-targeting UCNPs-based nanosystems capable of combination chemotherapy with PDT,as well as MR/UCL imaging,and studied their active targeting behavior and therapeutic efficacy in pancreatic cancer.The main work of the thesis could be summarized as follows:1.EpCAM-targeting rattle-structured upconversion core/mesoporous silica nanotheranostic systems were designed,and MX was encapsulated into the cavities,thus EpCAM-UCMSNs-MX was obtained.Besides,a series of characterizations and measurements were conducted to verify the success of design.2.Biocompatibility of EpCAM-UCMSNs was evaluated under series assays,and then good uptake and targeting efficiency in vitro were proved,subsequently in vivo UCL/MR images were acquired successfully.Biodistribution and targeting efficiency were also evaluated.3.In vitro and in vivo synergetic therapeutic experiments were performed,and these results excitingly demonstrated that the nanosystems endow synergetic chemotherapy and PDT under NIR excitation,holding great potential to the translation of clinical implications.