Nucleoside Analogues-Containing Precise Nanodrugs for Cancer Therapy

Author:Mou Quan Bing

Supervisor:yan de yue zhu xin yuan zhang chuan


Degree Year:2018





Nowadays,nucleoside analogues are an important kind of therapeutic agents for cancer therapy,which are widely used in clinic.However,small molecular nucleoside analogues still suffer from inherent limitations,such as short pharmacokinetics,low tumor accumulation,undesirable side effects,severe drug resistance and so on.To solve these problems,nanoscale drug delivery systems(DDSs)for the delivery of nucleoside analogues have gained much attention in recent years,which can achieve longer pharmacokinetics and higher tumor accumulation.Till now,various intelligent designs of DDSs for the delivery of nucleoside analogues have been carried out.However,most DDSs still lack of precise control over their chemical components and nanomorphologies,which greatly limits their large-scale fabrication and clinical evaluation.Therefore,there is an urgent demand for the development of precise nanoscale DDSs with definite chemical components and tunable nanomorphologies.To achieve these goals,we proposed the strategy of DNA Trojan horses to construct precise nanoscale DDSs for the delivery of nucleoside analogues.The main contents are described below.(1)Construction of(gemcitabine)10-based nanogels for cancer therapyTo develop precise nanoscale DDSs with definite chemical components and tunable nanomorphologies,we attempted to overcome these obstacles via a step-by-step process.Firstly,to achieve the goal of developing novel drug-containing nanogels with definite chemical components,nucleoside analogue therapeutic agent,gemcitabine,was integrated into DNA strands to fabricate polygemcitabine(Ge10)through conventional solid-phase synthesis.Thanks to the molecular interaction,Ge10 can self-assemble into nanogels in buffered solutions.As a novel drug delivery system,Ge10 nanogels can be efficiently uptaken by cancer cells,and thereafter release therapeutic agents to induce cell apoptosis.Besides,Ge10 nanogels can significantly accumulate in tumors and hence inhibit the tumor growth in vivo.Thanks to the precise control over chemical components and drug loading ratios,Ge10nanogels may act as promising candidates in cancer therapy for clinical applications.(2)Construction of two-in-one Chemogene assembled by drug-integrated antisense oligonucleotides to reverse chemoresistanceNucleoside analogue therapeutics can not only work as therapeutic agents for cancer therapy,but also can be endowed with other biological functions for their high precision recognition ability.Drug resistance is a common phenomenon and big challenge in cancer treatment.To overcome this issue of drug resistance,combinatorial chemo and gene therapy provides a promising way to cure drug-resistant cancer as the delivered functional nucleic acids can regulate the related genes,thereafter reversing the chemoresistance.However,the dramatic differences between chemotherapeutics and nucleic acids greatly hinder the design and construction of an ideal DDS that can exert the antitumor effects and regulate the drug-resistant genes synergistically.Here,we proposed a new approach to synthesize a nanoscale DDS using drug-integrated antisense oligonucleotides(named as Chemogene)for reversing drug resistance.As a proof of concept,nucleoside analogue floxuridine was integrated into the antisense sequence by replacing thymine inside.After conjugation to polycaprolactone,spherical nucleic acid(SNA)like Chemogene can be assembled.With the capability of rapid cell uptake without any transfection agents,this two-in-one Chemogene could induce the downregulation of the drug resistance-related genes,and subsequently release the therapeutic agents.As such,Chemogenes showed effective anticancer efficacy to both subcutaneous and liver tumor transplantation mouse model bearing drug-resistant tumors,demonstrating its great potential for a better combined cancer therapy.(3)Construction of floxuridine-containing DNA Trojan horses for cancer therapyWe proposed the strategy of drug-containing DNA Trojan horses to fabricate precision nanomedicine with both definite chemical components and tunable nanomorphologies.Based on the structural similarity,herein,nucleoside analogue therapeutics were integrated into DNA strands through conventional solid-phase synthesis.By elaborately designing their sequences,floxuridine-integrated DNA strands were synthesized and self-assembled into well-defined DNA polyhedra with definite drug loading ratio as well as tunable size and morphology.As a novel drug delivery system,these drug-containing DNA polyhedra could ideally mimic the Trojan Horse to deliver chemotherapeutics into tumor cells and fight against cancer.Both in vitro and in vivo results demonstrated that DNA Trojan Horse with buckyball architecture exhibited superior anticancer capability over the free drug and other formulations.With precise control over drug loading ratio and structure of the nanocarriers,DNA Trojan Horse may play an important role in anticancer treatment and exhibit great potential in translational nanomedicine.