Investigation Of Nanoscale Drug Delivery System For Targeting Tumor Cell And Tumor Microenvironment

Characteristics of tumor tissue,including heterogeneity,adaptability to external changes and egotism by orchestrating neighboring environment to support proliferation and metastasis,pose great challenges for precise,effective and thorough therapy of cancer.Traditional chemotherapy,radiotherapy and phototherapy rely on small molecule chemotherapeutic drugs,radiosensitizers and photosensitizers,which are confronted with poor solubility,short circulation time in the blood,and susceptibility to physiological degradation.Nanotechnology has emerged to achieve targeted delivery,improve half-life of drugs and protect cargos from being degraded before reaching tumor site due to its size effects,tailorable physiochemical properties,high bioavailability and limited side effects.Previous studies focused on delivering anti-cancer therapeutics to induce apoptosis of tumor cells directly,which indeed had favorable outcomes in a short period.However,residual tumor cells could experience recurrence and metastasis under the nourishment of tumor microenvironment,resulting in poor prognosis and decreased five-year survival rate.Under such circumstances,we herein investigated the multiple therapeutic modalities from the level of tumor cell to tumor microenvironment.We first developed a multistage drug delivery system based on cascaded aptamers to achieve precise treatment of tumor cells.Then a lipid droplet-based drug delivery system was proposed to augment therapeutic efficacy by taking advantage of the interaction mechanism between tumor cells and adipocytes.Further inspired by the behavior of tumor cells that could adapt and change tumor microenvironment,we designed a nanoframework that was capable of adapting and remolding tumor microenvironment to inhibit tumor growth and prevent metastasis.The investigation in our work may provide new perspective for precise,effective and thorough therapy of cancer and the specific content is summarized as follows:1.Precise drug delivery at cellular levelIn order to improve targeting efficacy and minimize side effect,we designed a multistage targeted drug-delivery system by employing the recognition capability and biocompatibility of aptamers to efficiently treat human epithelial growth factor receptor(HER2)-overexpressing breast cancer.In this nanovehicle,two aptamers respectively specific to HER2 and ATP were organized in a hierarchical manner.The outmost HER2 aptamer(HB5)governs the recognition to HER2 protein overexpressed in SK-BR-3 cell lines,while the ATP aptamer incorporated with anticancer drug(-)-epigallocatechin gallate(EGCG)and protamine sulfate in the inner core functions as a switch of drug release in response to abundant intracellular ATP.Subsequently,nanostructured lipid carriers(NLCs)were constructed to wrap and stabilize the loosely bounded inner core,minimizing premature drug leakage potentially encountered by the biomolecule assembled nanocarriers.This multiple biomolecules-enveloped nanovehicle demonstrated improved inhibitory actions on tumor growth and minimum side effect to normal organs and tissues both in vitro and in vivo,offering a promising drug-delivery platform with transport precision and biological safety.2.Lipid droplet-based drug delivery system taking advantage of the interaction mechanism between tumor cells and adipocytesBased on the fact that tumor cells have hyperactive crosstalk with adipocytes,we explored lipid droplet,an organelle from adipocytes,to function as a controllable and biocompatible vehicle to deliver anticancer drug.We validated that isolated lipid droplets maintained their key physiological functions to interact with other organelles and augmented the therapeutic effect of cancer photodynamic therapy by encapsulation with a lipid-conjugated photosensitizer(Pyrolipid)through a variety of pathways,including reactive oxygen species(ROS)generation,lipid peroxidation and endoplasmic reticulum(ER)stress.As such,the IC 50 value of Pyrolipid was reduced by 6.0-fold when loaded into the lipid droplet.Of note,in vivo results demonstrated that engineered lipid droplets induced significant inhibition effects of tumor growth with minimal side effects.3.Nanoframework inhibits tumor growth and metastasis via adapting and remolding TMEAbnormal tumor microenvironment(TME)not only facilitates tumor proliferation and metastasis,but also establishes physiological barriers for effective transport of therapeutics inside the tumor,posing great challenges for cancer treatment.Here we designed a core-satellite size transformable nanoframework(denoted as T-PFRT)that can synchronously adapt to and remold TME for augmenting photodynamic therapy to inhibit tumor growth and prevent tumor metastasis.Upon matrix metalloproteinase 2(MMP2)-responsive dissociation of the nanoframework in TME,the core structure loaded with TGF? signaling pathway inhibitor and oxygen-carrying hemoglobin aims to stroma remodeling and hypoxia relief,allowing the photosensitizer-encapsulated satellite particles to penetrate to deep-seated tumor for oxygen-fueled photodynamic therapy.We demonstrated that T-PFRT could overcome the stroma and hypoxia barriers for delivering therapeutics,and gain excellent therapeutic outcomes in the treatment of primary and metastatic tumors.