Construction And Antitumor Study Of Multifunctional Mesoporous Silica Nanomedicine/nanovaccine

Cancer is one of the diseases that seriously threaten human life and health,causing nearly 10 million deaths worldwide every year,and the morbidity and mortality of cancer are still increasing year by year.Currently,more than 90%of cancer-related deaths are caused by cancers that have spread to distant organs.Surgical resection,chemotherapy and radiotherapy are the most widely used cancer treatment strategies in current clinical treatment.However,surgical resection is usually accompanied by serious postoperative complications as well as tumor metastasis and recurrence.Chemotherapy and radiotherapy not only tend to make the patients’body resistant to chemotherapeutic drugs or radiation,thereby reducing the therapeutic effect,but also are easy to produce indiscriminate toxic side effects on normal tissues,causing huge physical and psychological trauma to the patients.Therefore,there is an urgent need to explore alternative therapeutic strategies that are novel,minimally invasive,and precise to meet clinical satisfaction.Photothermal therapy(PTT)and photodynamic therapy(PDT)are strategies that activate photothermal agents or photosensitizers under specific wavelengths of laser irradiation to induce hyperthermia or reactive oxygen species(ROS)-mediated cytotoxicity,respectively,which lead to tumor cell apoptosis.PTT and PDT have the advantages of less side effects and drug resistance,high selectivity and low invasiveness.It is worth mentioning that PDT has been used in clinic treatment of various cancers.Immunotherapy is a next-generation cancer treatment that is able to effectively suppress and kill tumors by activating and enhancing a patients’ immune system and has the advantages of strong specificity,low side effects,significant inhibition of tumor growth and prevention of tumor recurrence and metastasis.U.S.Food and Drug Administration(FDA)has approved a variety of immunotherapies for clinical use in recent years.PTT,PDT and immunotherapy are emerging as attractive antitumor treatment options,which are capable of achieving significant clinical outcomes while minimizing unbeneficial influence on patients.It has been found in a large number of clinical practice and exploratory studies that single treatment modality can’t eliminate the entire tumor and effectively prevent tumor recurrence and metastasis,which may be due to the complexity and heterogeneity of tumors that allow tumor cell subsets resistant to monotherapy present in tumor tissues.As a result,the advanced progress in tumor therapy has gradually transformed from monotherapy to combination therapy to achieve a synergistically enhanced therapeutic effect of "1+1>2".With the help of nanotechnology,the integration of two or more drugs in a single nanoplatform by physical adsorption and/or chemical binding is beneficial to avoid the disadvantages of monotherapy as well as increase drug stability and improve drug loading and release kinetics,thus achieving maximum therapeutic effect and minimum mortality.In addition,it is also necessary to introduce imaging capabilities when designing nanoplatforms,which can not only provide accurate tumor structure and location information,but also observe the distribution and metabolism of drugs in real time so as to formulate and adjust personalized treatment plans.Among numerous nanoplatformbased imaging-guided synergistic therapy systems(i.e.,nanotheranostic platforms),fluorescence(FL)imaging and/or ultrasound(US)imaging-guided PTT-PDT or PTTimmunotherapy synergistic treatment showed excellent diagnosis and therapy effect and application value.In view of these,the paper mainly carried out the following two parts of research work:The first part developed a nanotheranostic platform based on mesoporous silica nanoparticles(MSNs).Liquid perfluorohexane(PFH)was encapsulated into the pores of MSNs by negative pressure method and polydopamine(PDA)was coated on the surface of MSNs while the FDA-approved near-infrared fluorescent dye indocyanine green(ICG)was effectively chimed.After PEG-FA was chemically bound to the PDA layer,a nanotheranostic platform for FL/US dual-modal imaging guided PTT-PDT combined therapy was obtained(represented by MSNs-PFH@PDA-ICG-PEG-FA).Both in vitro and in vivo experiments demonstrated that the system was able to significantly improve the stability of ICG and overcome the shortcomings of ICG being susceptible to photobleaching.The system can be reserved in the tumor for a longer time compared to free ICG and achieve an effective temperature increase after multiple rounds of 808 nm laser irradiation.The system can also effectively enhance the uptake efficiency of ICG by tumor cells and the generation of intracellular ROS,and effectively kill tumor cells under the dual effects of hyperthermia and ROS.Under the irradiation of 808 nm near-infrared laser,ICG and PDA exhibited excellent combined photothermal effects.The temperature rise of local tumor would destroy the PDA layer and cause the "liquid-to-gas" transition of PFH,leading to the generation of microbubbles and thereby enhancing the effect of ultrasound imaging.Besides,ICG produced ROS to exert PDT property and directly kill tumor cells.Above all,under the guidance of US and FL imaging,PTT-PDT synergistic antitumor effects were achieved with cure rate of 60%in breast cancer-bearing nude mice,indicating the promising prospect of MSNs-PFH@PDA-ICG-PEG-FA as a multifunctional nanotheranostic platform.The second part designed a PDA-modified MSNs nanovaccine aiming at the problem that PTT alone cannot effectively inhibit tumor metastasis and recurrence.Ammonium bicarbonate(ABC)was physically loaded into the pores of MSNs,and the model antigen ovalbumin(OVA)was chemically linked to the PDA layer to obtain the final nanovaccine MSNs-ABC@PDA-OVA,which was able to fight against melanoma through photothermal combined immunotherapy.The PDA layer enabled the nanovaccine to efficiently convert light energy into heat under 808 nm near-infrared laser irradiation,thus directly killing primary tumor cells.Under the conditions of slight acidity and elevated temperature in the local tumor,the ABC encapsulated into the pores was decomposed into gas to accelerate the release of OVA from the nanovaccine and promote the escape of antigens from lysosomes of dendritic cells(DCs)to cytoplasm for cross-presentation.The MSNs-ABC@PDA-OVA nanovaccine plus 808 nm laser irradiation promoted the migration of the nanovaccine from the injection sites to the lymph nodes,significantly enhanced the activation and maturation of DCs in tumor-draining lymph nodes,and elicited robust antigen-specific cytotoxic T lymphocytes(CTLs)and helper T lymphocytes(Ths)responses,reduced the intratumoral infiltration of regulatory T cells(Tregs),thereby effectively improving the immunosuppressive tumor microenvironment.Of particular note,a single injection of MSNs-ABC@PDA-OVA plus a single round of 808 nm laser irradiation effectively eradicated the primary tumor with a 75%cure rate for B 16-OVA melanoma and prevented lung metastasis in cured mice.What’s more,the MSNsABC@PDA-OVA nanovaccine combined with PTT treatment induced a strong and enduring immune memory effect,equipping the body with the ability to resist tumor recurrence for a long time,and no tumor recurrence occurred during the observation period of up to 70 days.In conclusion,MSNs-ABC@PDA-OVA is a simple but effective therapeutic nanovaccine and provides new ideas for the treatment against melanoma,which could achieve significant efficacy against tumor growth,metastasis and recurrence without the use of additional checkpoint blockers or immunomodulators.