Preparation Of Polymer Microneedles For Transdermal Delivery And Light-induced Anti-melanoma

At present,as a form of skin cancer,the incidence of melanoma has gradually increased in the past few decades.Melanoma is becoming the leading cause of death of the skin,due to its high degree of malignancy,rapid progress,dangerous condition,and extremely poor prognosis.For the treatment of melanoma,traditional treatment methods such as surgery and chemotherapy have shown unsatisfactory results.However,some emerging treatment methods,such as photothermal therapy and chemodynamic therapy,have the advantages of good therapeutic effect,low systemic toxicity and small side effects.The microneedle transdermal drug delivery system,as a minimally invasive local drug delivery system with the dual release characteristics of subcutaneous injection and transdermal drug delivery,is more convenient,flexible and safer than intravenous injection or intratumoral injection.Such advantages have attracted wide attention from international scholars and medical workers.In this paper,different microneedle systems are designed,which can safely and effectively deliver multifunctional nano-drugs.The synergistic anti-tumor effect of the microneedle system is evaluated by establishing a melanoma mouse model.Specifically,the following three parts of research have been carried out:1.A separable microneedle transdermal drug delivery system for chemotherapy-photothermal therapy（CT/PTT）synergistic anti-melanoma was designed,and it was prepared by a two-step centrifugal inverted molding method.The photothermal performance characterization and cytotoxicity analysis of ICG by infrared thermal imaging camera showed that ICG was a photothermal agent with good biocompatibility and photothermal performance.CCK-8 was used to detect the in vitro cell survival rate of ICG/DOX under NIR excitation,and the results showed that ICG/DOX could significantly inhibit tumor cell growth under NIR excitation.The morphology of the microneedle was measured by digital microscope and scanning electron microscope（SEM）,which showed that the needle body presented an obvious two-stage structure.The mechanical properties of the universal testing machine were analyzed,and the mechanical strength was excellent enough to pierce the skin.The thermal performance was analyzed by infrared thermal imaging camera,showing good thermal performance,which could be used to release drugs and thermally ablate tumors.A nude mouse model of B16F10 melanoma was established,and the microneedle system was used to analyze the thermal damage to the skin of the microneedle system under NIR excitation by the infrared camera,and the small animal in vivo optical imaging system was used to analyze the drug distribution in the main organs of the tumor-bearing mice after the microneedle administration which showed that the microneedle administration was safe and reliable.Through the anti-tumor effect of different groups of tumor-bearing mice,the H&E and TUNEL stained sections of tumors showed that the two-segment separable microneedles loaded with DOX/ICG had obvious synergistic anti-tumor effects,which was a potential anti-tumor strategy.2.A core-shell type microneedle transdermal drug delivery system for photothermal-chemodynamic therapy（PTT/CDT）synergistic anti-melanoma was designed,and it was prepared by vacuuming and thermal melting.TEM-mapping and X-ray photoelectron spectroscopy（XPS）analysis showed that polydopamine nanoparticles（Cu-PDA NPs）doped with Cu（II）were successfully synthesized.The photothermal performance of Cu-PDA NPs was characterized by infrared thermal imaging camera,and the Fenton-like catalytic activity produced by Fluorescence Spectroscopy（SF）and Electron Spin Resonance（ESR）was detected under simulated in vitro H₂O₂environment to produce·OH and cytotoxicity analysis.It showed that Cu-PDA NPs was a kind of nanometer anti-tumor drug with good biocompatibility and multifunctionality.CCK-8 was used to detect the in vitro cell survival rate of Cu-PDA NPs under NIR light excitation,indicating that Cu-PDA NPs could significantly inhibit tumor cell growth under NIR excitation.Its thermal performance was analyzed by infrared thermal imaging camera,showing good thermal performance,which could be used for thermal ablation of tumors.A nude mouse model of B16F10melanoma was established,and the Cu-PDA NPs microneedle system loaded with an infrared camera was used to analyze the skin heat damage,blood routine,blood biochemistry,and acute toxicity in vivo under the excitation of NIR light,which showed that the microneedle delivery system was safe and reliable.Through the anti-tumor effect of different groups of tumor-bearing mice,H&E and TUNEL stained sections of tumors,the results showed that the core-shell microneedles loaded with Cu-PDA NPs had obvious synergistic anti-tumor effects and were a potential anti-tumor strategy.3.A core-shell type microneedle transdermal drug delivery system for PTT/enhanced CDT synergistic anti-melanoma was designed,and it was prepared by vacuuming and thermal melting.TEM-mapping,XPS and X-ray diffraction（XRD）analysis showed that polydopamine-coated calcium peroxide nanoparticles（CaO₂@Mn（Ⅱ）-PDA NPs）doped with Mn（II）were successfully synthesized.The photothermal performance characterization of CaO₂@Mn（Ⅱ）-PDA NPs by infrared thermal imaging camera,ESR detection of Fenton-like catalytic activity to produce·OH and cytotoxicity analysis showed that CaO₂@Mn（Ⅱ）-PDA NPs was a kind of organism good compatibility,multifunctional nano anti-tumor drugs.The in vitro cell survival rate of CaO₂@Mn（Ⅱ）-PDA NPs under NIR light excitation was detected by CCK-8,which showed that CaO₂@Mn（Ⅱ）-PDA NPs could significantly inhibit tumor cell growth under NIR light excitation.Through infrared thermal imaging（MR）analysis of its thermal performance,it showed good thermal performance and could be used for thermal ablation of tumors.A nude mouse model of B16F10 melanoma was established.The internal organs of the tumor-bearing mice with microneedles were detected by MRI and the concentration of Mn²⁺was detected by atomic absorption spectroscopy（AAS）.The results showed that the microneedle drug delivery system was safe and reliable.Through the anti-tumor effect of the tumor-bearing mouse group,the tumor H&E and TUNEL staining section analysis,the results showed that the core-shell microneedle loaded with CaO₂@Mn（Ⅱ）-PDA NPs had obvious synergistic anti-tumor effect,which was a potential Anti-tumor strategy.