Responsive Polymeric Nanocarriers For Overcoming Drug Resistance Of Cancers And Applications

Responsive polymeric nanocarriers have been widely explored to use in the treatment of tumors in recent years.Compared with traditional drug therapy to tumors,responsive polymer nanocarriers can solve the problems of anticancer drugs with poor water-solubility,limited stability,low targeting ability,limited dosing,toxic side effects and drug resistance,greatly improve the tumor therapy efficiency.Polymeric nanocarriers as drug delivery systems can deliver drugs through physical encapsulation or chemical conjugation to improve the solubility and physiological stability of anticancer drugs.Meanwhile,due to the hyper-vascular density around tumor tissue,the wide vascular wall space,and poor integrity of vascular structure,polymeric nanocarriers can accumulate into tumor tissues via well-known EPR Effect(the Enhanced Permeability and Retention Effect),which improves targeting efficiency and reduces toxic side effects of anticancer drugs.Utilizing the specific differences between normal tissues and tumor tissues,responsive polymeric drug nanocarriers can realize the controllable drug release at the action sites.Thus,the well-designed polymeric nanocarriers could reach to tumor sites via long term blood circulation,which improves the tumor accumulation of anticancer drugs and may overcome drug resistance towards tumor cells.Our work was divided into two parts.Part 1:To overcome the drug resistance in chemotherapy,our work mainly focused on the design of responsive polymeric nanocarriers to improve the delivery efficiency and reverse the drug resistance of tumor cells for maximizing the therapeutic efficacy and minimizing the side effects.Part 2:To overcome the limitations of tumor hypoxia environment in photodynamic,the responsive polymeric nanocarriers was designed to achieve the photodynamic therapy to tumors without the participation of oxygen.This paper mainly includes the following four parts:1.Responsive polymeric micelles were prepared to overcome cisplatin drug resistance towards cancers via depletion of cellular glutathione.We designed an amphiphilic diblock copolymer composed of poly(ethylene glycol)(PEG)and polymerized phenylboronic ester-functionalized methacrylate(PBEMA),PEG-b-PBEMA,which can self-assemble into responsive polymeric micelles in aqueous solutions to load hydrophobic cisplatin prodrug(Pt(IV)).Under the stimulation of endogenous hydrogen peroxide in tumor cells,the PBEMA part of polymer micelles decomposed to quinone methyl,which can react with intracellular glutathione(GSH)and reduce the level of cellular GSH.Meanwhile,with the transition of PBEMAmoiety from hydropholic to hydrophilic,the polymer micelles swelled gradually,which promoted the reduction of tetravalent platinum to the original cisplatin by intracellular reducing agent ascorbic acid and achieved the controlled release of the drugs.Pt(IV)-loaded PEG-b-PBEMA micelles(PtBE-Micelle)reverse cisplatin-resistance of cancer cells through improving cellular uptake efficiency and reducing the detoxification effect of intracellular GSH on cisplatin.Responsive polymeric micelles(PtBE-Micelle)displayed significantly higher cytotoxicity than cisplatin toward A549R cells and inhibited the growth of A549R xenograft tumors effectively.2.Responsive polymeric nanoreactors were prepared to overcome cisplatin drug resistance via production of H2O2.We synthesized tumor pH-responsive block copolymers poly(ethylene glycol)-b-poly[benzyl methacrylate-co-2-(piperidin-1-yl)ethyl methacrylate],PEG-b-P(BzMA-co-PEMA),which can self-assemble into vesicular nanoreactors to codelivery glucose oxidase(GOD)and cisplatin(Cis/GOD@Bz-V).After accumulation into tumor sites,the permeability of nanoreactor membranes was increased owing to the protonation of PPEMA moiety,which resulted in the release of cisplatin and the production of H2O2 with oxidation reaction of diffused glucose and O2 under the catalysis of GOD.The generation of H2O2 could activate intracellular pro-apoptotic pathways to reverse resistance of cisplatin and increase the cytotoxicity of cisplatin towards cancer cells.Responsive polymeric nanoreactors Cis/GOD@Bz-V can kill cisplatin-resistant A549R cells and inhibit the growth of A549R xenograft tumors more effectively.3.Responsive core cross-linked polymeric micelles(CCL)based on cypate and cisplatin prodrugs-conjugated block copolymers were prepared to realize synergistic photothermal-chemotherapy of cancers and overcoming drug resistance.The block copolymers,poly[2-(2-methoxyethoxy)ethyl methacrylate)-co-(N-methacryloxy succinimide)]-b-poly(N-(2-hydroxypropyl)methacrylamide)(P(MEO2MA-co-MASI)-b-PHPMA),were synthesized via reversible addition-fragment chain transfer(RAFT)polymerization.After partial aminolysis of succinimide with 3-azidopropylamine,the alkynyl-functionalized cypate and Pt(IV)complex were conjugated via click reaction.The CCL were fabricated by core cross-linking in aqueous solution using cystamine as the cross-linker.The CCL micelles showed stability in the physiological environment and controlled cisplatin drug release in tumor cells.The conjugated cypate molecules in the cores of CCL micelles resulted in photothermal temperature increase and overcoming drug resistance under an 805 nm near infrared(NIR)laser irradiation.Significant synergistic effect of photothermal therapy and chemotherapy was demonstrated against cisplatin=resistant human lung cancer cells A549R under NIR irradiation.4.The rationally designed tumor pH-responsive polymeric micelles are devised to realize oxygen-independent combined PDT and photothermal therapy(PTT)under near-infrared light(NIR)irradiation.The triblock copolymer,poly(ethylene glycol)-b-poly(e-caprolactone)-b-poly(2-(piperidin-1-yl)ethyl methacrylate)(PEG-b-PCL-b-PPEMA),was prepared to co-encapsulate cypate and singlet oxygen donor(diphenylanthracene endoperoxide,DPAE)via self-assembly to obtain the polymeric micellar delivery system(C/0@N-Micelle).C/O@N-Micelle showed remarkable tumor accumulation and improved cellular internalization as the pH value was changed from 7.4 during blood circulation to 6.8 in tumor tissues.The micelles could produce a potent hyperthermia for PTT of cypate under 808 nm NIR irradiation,which simultaneously induced thermal cycloreversion of DPAE generating abundant singlet oxygen for PDT without tumorous oxygen molecules participation.The photothermally triggered combined PDT and PTT achieved efficient tumor ablation without systemic toxicity in an oxygen-independent manner.Responsive polymeric nanoparticles as carriers of anticancer drugs and photosensitizers for chemotherapy and optical treatment of tumors can solve the defects of the separate use of anticancer drugs and photosensitizers,overcome drug resistance in tumors,and finally improve the cure index of tumors,which has a promising application prospect in clinical tumor treatments.