Degradable Polymeric Nanodrug Delivery System For Antitumor Effects

Degradable polymers have great research value and application prospects as drug carriers for oncology therapy.Polymeric drug carriers can significantly improve the bioavailability of chemotherapeutic drugs,increase targeting,and reduce non-specific systemic toxicity,thus improving therapeutic efficacy.However,it remains a great challenge to effectively design and synthesize degradable polymers according to the tumor microenvironment.This thesis focuses on the design and construction of various degradable polymer drug delivery systems and their application as nano-drug carriers in tumor treatment process.The research of this thesis is divided into three main parts:1.A novel monomer and polymerization system for phosphate ester polymerization was developed.The reaction of trichlorothiophos with ethylene glycol was to obtain a functionalized five-membered cyclic thiophosphoryl chloride(CTP),which in turn reacts with alkyl alcohols of different carbon chain lengths in the presence of triethylamine to form phosphorothioate monomers:methyl ethyl phosphorothioate(MTP),ethyl ethyl phosphorothioate(ETP),n-propyl ethyl phosphorothioate(PTP),n-butyl ethyl phosphorothioate(BTP).The ring-opening polymerization was initiated with benzyl alcohol,and a series of catalysts and catalytic conditions were screened to finally obtain the conditions for the controlled polymerization of these phosphorothioates.The obtained homopolymers were subjected to differential scanning calorimetry(DSC)and thermogravimetric analysis(TGA)to obtain their glass transition temperatures and thermal decomposition temperatures.This thiophosphate has a lower glass transition temperature and a higher thermal decomposition temperature compared to the conventional polyphosphate.Subsequently,polyethylene glycol(mPEG2k-OH)and hydroxyl capped polycaprolactone(PCL-OH)were used as initiators to trigger the polymerization of phosphorothioate monomers to obtain a two-block copolymer.The poly(ethylene glycol)-b-poly(ethylene ethylene propyl phosphate)(mPEG-b-PETP)was able to self-assemble in aqueous solution to form nanoparticles,and the poly(phosphorothioate)was found to have stronger hydrophobicity by light scattering(DLS)and critical micelle concentration(CMC)experiments.The degradation ability of the carriers was subsequently examined by size exclusion chromatography(SEC),and the mPEG-b-PETP exhibited very good resistance to hydrolysis in solutions with different pH of acidity and alkalinity.However,in the presence of hydrogen peroxide,thiopolyphosphate was able to degrade rapidly,and this specific degradation pattern gave a new idea for responsive drug release.2.A nano-drug carrier(NPHpaPN)based on a natural polymeric hyaluronic acid(HA)backbone in response to tumor hypoxic microenvironment was established.This drug carrier achieves tumor tissue killing by bonding a cisplatin prodrug,while exploiting the tumor hypoxia response leading to the action of hyaluronic acid and CD44 receptors on the tumor cell surface to increase the ability of the drug carrier to enter chemotherapy-tolerant cells in the hypoxic region,and the encapsulated DNA damage repair inhibitor can significantly inhibit the nucleoside shear repair pathway of tumor cells,thus promoting tumor cell death.Cisplatin prodrug(Pt-C12)and a hypoxia-responsive polyethylene glycol(PEG-azo)were used to encapsulate DNA repair inhibitor NERi into nanoparticles by esterifying with carboxyl groups on the HA backbone to obtain polymer HPaP using ultrasonic dispersion.This drug carrier has excellent cellular uptake and cytotoxicity under in vitro simulated hypoxic conditions.In in vivo experiments,the carrier was enriched to tumor tissues by enhanced permeation and retention(EPR)effects and increased HA-CD44 by shedding the PEG shell layer under depleted oxygen conditions,facilitating its penetration in tumor depleted sites.In therapeutic experiments,NPHPaPN significantly inhibited tumor growth compared to cisplatin.This vector design for overcoming the problem of drug resistance due to tumor heterogeneity provides ideas for the use of nanomedicines in tumor chemotherapy.3.Copper ions play a role in maintaining oxidative phosphorylation in tumor growth,which would provide the energy necessary for cell growth,and biomass synthesis.Based on this concept,a one-pot synthesis of dendrimers with specific group functionalization on their surface was established to enable them to adsorb copper ions from the blood circulation,thus limiting the copper ion supply to the tumor.Using trimethylolpropane as the growth core of the dendrimer,the dendrimer was reacted with IEMA and 1-TG in turn under suitable catalyst and catalytic conditions to finally obtain the dendrimer TMP-G4-OH.The copper ion ligand group(CDM-COOH)and polyethylene glycol carboxyl group(mPEG-COOH)were subsequently grafted on its surface to obtain the copper ion adsorbed drug.We examined the ability of TMP-G4-CDM-PEG to adsorb Cu from the environment at the nanoparticle level,cellular level,and animal level,respectively,and the reduction of Cu in the environment was demonstrated by fluorescence changes of monovalent and divalent Cu probes and direct detection of metal elements.Finally,we evaluated the anti-tumor effect of TMP-G4-CDM-PEG and found that Cu limitation significantly slowed down the tumor growth rate and that TMP-G4-CDM-PEG was more effective than the clinically used copper chelator tetrathiomolybdate(TM).