Construction of Nano-based Drug Delivery Systems with Precise Components for Cancer Therapy

Author:Ma Zuo

Supervisor:zhu xin yuan yan de yue zhang chuan

Database:Doctor

Degree Year:2018

Download:24

Pages:144

Size:8201K

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With the rapid development of nanotechnology,nanodrug is becoming an important dosage form.After decades of hard work,various nanodrugs,such as micelles,vesicles,nanogels,inorganic nanoparticles,protein-based nanoparticles,and DNA-based nanoparticles have been carried out.These nanodrugs are widely used in drug delivery,gene transfection,etc.for cancer therapy.However,batch-to-batch variations appearing in nanodrugs greatly limit their clinic translation.Thus,it is a great challenge to construct nanodrugs with precise components.Inspired by the idea of amphiphilic drug-drug conjugates to prepare nanomedicines with presise components,herein we successfully constructed a series of similar nanodrugs for enhanced anti-cancer drug delivery both in vitro and in vivo.This dissertation can be divided into three major sections,and the main research contents and conclusions are shown as follows: 1.Construction of nanodrugs with precise components for targeted cancer therapyTargeted drug delivery is a broadly applicable approach for cancer therapy.However,most nanocarrier-based targeted delivery systems suffer from batch-to-batch variation,quality concerns,and carrier-related toxicity issues.Thus,to develop a carrier-free targeted delivery system with nanoscale characteristics is very attractive.Herein,a novel targeting small molecule nanodrug self-delivery system consisting of targeting ligand and chemotherapy drug was constructed,which combined the advantages of small molecules and nano-assemblies together and showed excellent targeting ability and long blood circulation time with well-defined chemical structure,high drug loading ratio and on-demand drug release behavior.As a proof-of-concept,lactose(Lac) and doxorubicin(DOX) were chosen as the targeting ligand and chemotherapy drug,respectively.Lac and DOX were conjugated through a pH-responsive hydrazone group.For its intrinsic amphiphilic property,Lac-DOX conjugate could self-assemble into nanodrugs with precise components in water.Both in vitro and in vivo assays indicated that Lac-DOX nanoparticles exhibited enhanced anticancer activity and weak side effects.This novel active targeting nanodrug delivery system shows great potential in cancer therapy.2.Construction of traceable nanodrugs with precise components for cancer therapyNano drug delivery systems have emerged as promising candidates for cancer therapy,whereas their uncertainly complete elimination from the body within specific timescales restricts their clinical translation.Compared with hepatic clearance of nanoparticles,renal excretion of small molecules is preferred to minimize the agent-induced toxicity.Herein,we construct in vivo renal-clearable nanoparticles,which are self-assembled from amphiphilic small molecules holding the capabilities of magnetic resonance imaging(MRI) and chemotherapy.The assembled nanoparticles can accumulate in tumor tissues for their nano-characteristics,while the small molecules dismantled from the nanoparticles can be efficiently cleared by kidneys.The renal-clearable nanoparticles exhibit excellent tumor-inhibition performance as well as low side effects and negligible chronic toxicity.These results demonstrate a potential strategy for small molecular nano drug delivery systems with obvious anticancer effect and low-toxic metabolism pathway for clinical applications.3.Construction of floxuridine-containing nanogels with precise components for cancer therapyDiverse nucleic acid nanostructures for biological usage have been engineered in the past decades.These nucleic acid nanoassemblies can efficiently load therapeutic agents to achieve excellent therapeutic effect.However,most nucleic acid based drug delivery systems(DDSs) still have limitations,including(1)complicated design and sophisticated fabrication;(2)lack of control over chemical composition and drug loading ratio(DLR)through non-covalent drug loading method;(3)drug incorporation may induce change in structural feature and loss of biostability.These limitations may hamper the clinical translation of nucleic acid-based DDSs.Thus,it is urgent to develop novel nucleic acid based DDSs to solve the aforementioned limitations.Herein,we report the self-assemblies of floxuridine-containing DNA nanogels and RNA nanogels with precise drug loading ratio as effective drug delivery systems.Based on the structural similarity between floxuridine(F) and thymidine,F can be incorporated into nucleic acid strands via either solid-phase synthesis or enzyme-mediated transcription.These F-integrated DNA or RNA strands with specific sequences can be used as building units and further assemble into nucleic acid based spherical nanogels,which can be efficiently uptaken by cancer cells and then release the therapeutic agents.As such,the drug-containing nucleic acid nanogels exhibit excellent inhibitory activity against cancer cells