Multifunctional Imaging-guided Theranostic Nanosystems Based On MSNs For Cancer Therapy

Mesoporous silica nanoparticles?MSNs?have long since been investigated to provide a versatile drug delivery platform due to its multitudinous merits.Particularly,mesoporous silica nanorods?MSNRs?and lipid bilayer coated MSNs have attracted great interest because of their better cell internalization capacity,higher drug loading properties and excellent biocompatibility.Besides,the combination of photodynamic therapy?PDT?and photothermal therapy?PTT?holds great promise to overcome respective limitations of the anti-cancer treatment.Firstly,in this work,we herein report Au nanorods?AuNRs?capped and Chlorin e6?Ce6?-doped mesoporous silica nanorods?AuNRs-Ce6-MSNRs?for the single-NIR light triggered combined phototherapy.AuNRs-Ce6-MSNRs are not only able to generate hyperthermia to perform PTT effect based on the AuNRs,but also can produce singlet oxygen?¹O₂?for PDT effect based on Ce6 after uncapping of AuNRs under the single NIR wavelength irradiation.In addition,the combined therapy can be dual-imaging guided by taking the photoacoustic?PA?imaging of AuNRs and NIR fluorescence?NIRF?imaging of Ce6.What's more,by utilizing the special structure of MSNRs,this nanocarrier can serve as a drug delivery platform with high drug loading capacity and enhanced cellular uptake efficiency.The multi-functional nanocomposite is designed to integrate photothermal and photodynamic therapy,in vivo dual-imaging into one single system,achieving synergistic anti-tumor effects both in vitro and in vivo.The AuNRs-Ce6-MSNRs aqueous solution performed an outstanding ability to increase temperature under NIR irradiation,verifying their excellent PTT effect.In addition,in vitro ¹O₂ generation experiment exhibited favorable results of PDT effect produced by AuNRs-Ce6-MSNRs under NIR irradiation stimulation.In vitro cellular studies contained cellular uptake study and cytotoxicity study?MTT and co-stain study?further confirmed that AuNRs-Ce6-MSNRs could enhance the uptake amount of drugs and own better ability to generate cytotoxicity to treat cancer cells through combined therapy effect.Further,in thermal imaging in vivo,the tumor temperature of AuNRs-Ce6-MSNRs treated group exceeded 50°C within 5 min under NIR irradiation,illustrating admirable PTT effect.In addition,in the results of fluorescence biodistribution and photoacoustic tomography,revealing AuNRs-Ce6-MSNRs had targeting effect and the excellent functions to guide dual-model imaging for cancer diagonosis.What's more,in animal experiments,AuNRs-Ce6-MSNRs treated group experienced the smallest tumor volume,tiny weight change with relatively stable tendency and relative higher survival.H&E stained experiment also showed the tumor tissue in AuNRs-Ce6-MSNRs group had the most significant damage.These results all demonstrated that the combined therapy of AuNRs-Ce6-MSNRs had prodigious efficiency to treat cancer and comparative slight toxicity,encouragingly.Secondly,gadolinium?Gd?,a T1 magnetic resonance?MR?imaging contrast agent,was doped into MSNs as a newly emerging theranostic nanocomposite,which has received much research attention.However,it is still concerned about the MSNs dispersibility and drug leakage.Hence,in this project,we constructed an NIR irradiation triggered,triple-modal imaging guided nanoplatform based on doxorubicin?DOX?@Gd doped-MSNs,conjugating with indocyanine green?ICG?loaded thermosensitive liposomes?designated as DOX@GdMSNs-ICG-TSLs?.In this platform,ICG could contribute to PDT and PTT effect,meanwhile,it could also give play to NIRF imaging and PA imaging.Hence,NIRF and PA imaging from ICG combined with the MR imaging function of Gd,devoted to triple-model imaging with success.Besides,folic acid?FA?modified thermosensitive liposomes were explored to coated onto the surface of DOX@GdMSNs to solve the DOX leakage as well as improve cellular uptake.Under the NIR irradiation,ICG could generate heat,leading to the rupture of ICG-TSLs.As consequence,DOX was released from GdMSNs.Therefore,the multifunctional nanocomposite appears to be a promising meritorious theranostic nanoplatform to pave a way for cancer.The experiment data showed that under 808 nm laser irradiation,DOX@GdMSNs-ICG-TSLs had the most excellent ability to increase temperature in all groups with the photothermal conversion efficiency???of 11.72%,verifying the preferable PTT effect of DOX@GdMSNs-ICG-TSLs.What's more,by the helping of1,3-diphenyl isobenzofuran?DPBF?under NIR irradiation,¹O₂ generation of DOX@GdMSNs-ICG-TSLs was detected.The absorption changes of DPBF in UV-vis spectra was dramatic for AuNRs-Ce6-MSNRs group,illustrating DOX@GdMSNs-ICG-TSLs has favorable PDT effect.Cellular uptake studies showed that DOX@GdMSNs-ICG-TSLs were mainly distributed in the cellular cytoplasm.And cellular cytotoxicity studies experiments demonstrated that DOX@GdMSNs-ICG-TSLs with synergistic therapy owned PTT and PDT effect,performed the best ability to kill cancer cells.After intravenous injection of DOX@GdMSNs-ICG-TSLs,in vivo NIRF,PA and MR imaging all showed the strongest signal at tumor site,revealing DOX@GdMSNs-ICG-TSLs had targeting effect and the outstanding functions to guide multi-model imaging for cancer diagonosis.What'more,thermal images and therapeutic efficacy studies,gave the results that DOX@GdMSNs-ICG-TSLs treated group gave the best behavior of anti-tumor effect with slight toxicity.In conclusion,these two smart nanosystems which contain combined therapy and imaging guided functions,might become suitable drug delivery nanosystem as imaging-guided therapeutic tools for cancer.