Construction Of Aza-BODIPY-Based Supramolecular Nanosystems And Their Application In Combined Tumor Therapies

Phototherapy includes photodynamic therapy（PDT）and photothermal therapy（PTT）which becomes increasingly widespread in anti-tumor research and application in recent years for the advantages of non-interference,no drug resistance,and low toxicity.However,due to the complexity and heterogeneity of the tumor,the monotherapy has limited anti-tumor efficacy.Research shows that different therapeutic mechanisms combined therapy could overcome the limitations of single mode therapy and effectively improve the antitumor efficacy.The new generation of fluorescent molecule Aza-BODIPY not only has the advantages of high photostability,high molar extinction coefficient,high phototoxicity,and low dark toxicity,but also has dual phototherapy activity,which has broad application prospects in the construction of phototherapy anti-tumor nanosystem,but its hydrophobicity could affect the bioavailability and delivery efficiency.The development of nano-delivery systems provided multiple effective ways for the hydrophobic molecules delivery.Among them,the supramolecular nano delivery system could introduce the hydrophilic groups by non-covalent interactions which would not only improve the delivery efficiency and bioavailability but also have the characteristics of a simply prepared process and flexible assembly methods.So,it has outstanding advantages in the construction of combination therapy required multi-drug co-delivery nanosystem.This paper utilizes supramolecular self-assembly nanotechnology to construct two Aza-BODIPY-based multifunctional supramolecular nanosystems,which could achieve the Aza-BODIPY efficient delivery and the combination therapies-enhanced anti-tumor effect.The specific results are as follows:1.Construction of S...S non-covalent bond-induced super-amphiphilic nanosystem and its application in the combination therapy of phototherapy-targeted therapy.A disulfide bond containing hydrophobic molecule BG（pro-drug（Gef）-photosensitizer（BOD））and hydrophilic molecule Lac-SS-Lac（dimer lactose）were synthesized and assembled to amphiphilic supramolecular nanoparticles BG-L NPs by intermolecular S…S bond induced supramolecular self-assembly.The DLS,SEM,and TEM proved that BG-L NPs were uniform spherical nanoparticles（PDI=0.220）with a particle size of 241 nm and a Zeta potential of-19.0 mV.The results of UV spectroscopy,HPLC,and LC-MS showed that BG-L NPs could respond to GSH and release BOD and Gef.BG-L NPs could achieve targeted delivery,and the ROS production was higher than BOD.The cytotoxicity results showed that the cytotoxicity of BG-L NPs was significantly higher than Gef and BOD under illumination.2.Construction of Aza-BODIPY-Cu-based supramolecular nanosystem and its application in the combination therapy of phototherapy-chemodynamic therapy（CDT）.Carboxyl-modified Aza-BODIPY（BOD-COOH）was synthesized and self-assembled with Cu²⁺to obtain the nano metal-photosensitizer BOD-Cu NPs.XPS analysis identified Cu²⁺in BOD-Cu NPs could consume the GSH and be used as an active center of CDT.The pyridine-modified glucose derivative was covered on the surface of BOD-Cu NPs through electrostatic interaction to form a glycosylated nano metal-photosensitizer BOD-Cu@G.DLS,SEM,and TEM analysis proved that the particle size of BOD-Cu@G was 302 nm,the Zeta potential was-20.2 mV and the particle size distribution was uniform.BOD-Cu@G consumed GSH and produced singlet oxygen（¹O₂）and hydroxyl radical（·OH）at the same time.The results of the cytotoxicity test showed that BOD-Cu@G has a stronger anti-tumor effect than BOD-COOH under illumination.Photothermal imaging results showed that BOD-Cu@G was most abundant in the tumor of H22 tumor-bearing mice after 24 hours of injection.The tumor basically disappeared and did not recur in the BOD-Cu@G group by the combined anti-tumor effect of CDT-enhanced phototherapy.In summary,this article constructs two Aza-BODIPY-based nano drug delivery systems by supramolecular self-assembly for anti-tumor combination therapy,which expands the application of Aza-BODIPY in the construction of super amphiphilic self-assembly nanosystems and nano metal photosensitizers,meanwhile provides a simple and efficient new platform for the Aza-BODIPY efficient delivery and the combination therapy enhanced anti-tumor application.