A PH-Sensitive Self-Assembled And Carrier-Free Nanoparticle Based On Charge Reversal For Enhanced Synergetic Chemo-Phototherapy

Nowadays,cancer is still one of the terrifying diseases globally.Chemical entities with disadvantages of off-target toxicity,poor water solubility,short half-life,and drug resistance,have greatly reduced the treatment effect.For example,Doxorubicin,the commonly used anticancer drug,is likely to cause serious side effects and induce multidrug resistance that reduced the efficiency of chemotherapy.Therefore,with the development of science and technology,more and more researchers pay attention to the nano-sized particles that have colloidal stability,active targeting ability or intelligently response to tumor microenvironment.However,there are remain crucial problems that hinder the development of the treatment,such as the complex formulation process,low drug loading capacity,batch-to-batch variation,the possible toxicity caused by carriers on the process of degradation,metabolism and excretion.In addition,it is remaining a challenge that ligands conjugated on the NPs surface with proper amounts achieve the most effective tumor accumulation and minimize nonspecifi c binding.The microenvironment-responsive carrier-free drug delivery system has many advantages,such as higher drug-loading content,simple preparation process,targeted drug delivery system,reduced toxicity,improved therapeutic efficiency,real-time monitoring drug distribution in vivo and so on.Due to the variation of pH between tumor microenvironment(pH 6.5-7.4)in extracellular environment of tumors and(pH 4.5-6.5)intracellular environment)and physiological environment(pH≈7.4),pH-responsive charge-reversal nanoparticles(one of the intelligently responsive nanoparticles)has great potential for suppressing the growth of cancer cells.Therefore,a novel charge-reversal nanoparticle drug delivery system was prepared for tracking drug distribution and effectively eradicating tumors by a chemo-and photo-therapy without recurrence during one treatment cycle.Doxorubicin(Dox)is employed among a wide range of solid tumors,Zinc phthalocyanine(ZnPc)which is the second-generation photosensitizer with excellent capability in FL/PA imaging and phototherapy.Dox and ZnPc can be exploited for the preparation of self-assemble Dox-ZnPc complex by non-covalent force(π-π stacking and hydrophobic interaction),which called DZ nanoparticles.Then,trace amount PDMAEMA-PHB-PDMAEMA was applied to modify the surface structure of DoxZnPc complex,which named DZP nanoparticles.PDMAEMA-PHB-PDMAEMA,with two hydrophilic poly blocks and a central hydrophobic poly block,has richly tertiary amino groups that is simple to protonate in acid conditions.Therefore,this novel nanoparticle could stay stable during the physical circulation,and play the behavior of charge reversal in the tumor acid environment to greatly decrease the interaction with plasma proteins electrostatic force or the cytotoxicity to normal cells.