NIR-Ⅱb Photodynamic And Chemotherapy Combined Therapy Platform Based On Rare-Earth-Doped Nanoparticles

Photodynamic therapy（PDT）can kill tumor cells after the photosensitizers absorbing excitation photons and producing reactive oxygen species.Compared with traditional treatment methods,PDT exhibits lots of advantages such as minimal side effects and low drug resistance,which has attracted increasing attention in recent years.However,the following problems seriously restrict its practical application:（1）It suffers from low therapy efficiency because of the diversity,heterogeneity and recurrence of tumors;（2）It is difficult to penetrate biological tissue because of the short excitation wavelength of most photodynamic therapy platforms（located in the visible light region or the first near-infrared region）.Combining PDT with chemotherapy to build a combined therapy platform is an effective strategy to improve therapy efficiency;Meanwhile,because the light scattering effect decreases with the increase of wavelength,red-shifting the excitation light to NIR-Ⅱb（1500-1700 nm）can significantly improve tissue penetration to reach deep tumor tissue.Therefore,developing NIR-Ⅱb photodynamic/chemotherapeutic combined therapy platforms is crucial to overcome above challenges.Rare earth-doped nanoparticles（RENPs）are characteristic of large Stokes/anti-Stokes shifts and multiple emission peaks,which can emit upconversion fluorescence（UCL）in the visible light region after absorbing multiple NIR-Ⅱb photons.Due to the visible light-excitable property of traditional photosensitizers,RENPs are ideal materials for developing NIR-Ⅱb PDT platforms.In addition,RENPs can emit down conversion fluorescence（DCL）in NIR-Ⅱb under near-infrared excitation,which can monitor the metabolism of the material in real-time and guide tumor therapy.Herein,we developed a combined therapy platform combining PDT photosensitizer excited by NIR-Ⅱb and chemotherapeutic drug released by tumor microenvironment.The main content is as following:In this paper,based on the NIR-Ⅱb-excitable properties and the ability to emit UCL of Er³⁺,RENPs with a structure of NaEr F₄@NaYF₄ was synthesized.Though modulating Tm³⁺concentration and the thickness of inert shell,the UCL intensity was enhanced by more than 10times.To achieve water-dispersibility,RENPs was coated by an amphiphilic polymer DSPE-PEG-FA,which can further load photosensitizer Ce6 and chemotherapeutic drug doxorubicin（DOX）through hydrophobic-hydrophobic interaction.The obtained nano platform can successfully produce cytotoxic ROS under irradiation of 1550 nm laser;In addition,the amino group of DOX was protonated in the acidic microenvironment of the tumor,leading to a significant decrease of hydrophobicity,resulting the releasing of DOX.Moreover,folic acid（FA）can bind to its folate receptors,which overexpressed on the surface of tumor cells,enabling the material to target tumor.The results of in vitro and in vivo experiment proved that the combined therapy platform can successfully kill tumor cells and inhibit tumor growth,which is expected to become a powerful tool for cancer treatment.