A Robust Chemo-phototherapy Nanoplatform Via Co-assembling Strategy Of Biotin-tailored IR780 And Quercetin

Phototherapy has received more and more attention due to its advantages of non-invasiveness and real-time fluorescence tracking of drug delivery,including photothermal therapy(PTT)and photodynamic therapy(PDT).Photothermal or photodynamic agents accumulating in tumor microenvironment(TME)can be activated under the irradiation of external light sources and then produce local hyperthermia or reactive oxygen species(ROS),thus exerting antitumor effects.However,phototherapy-treated tumor cells can rapidly result in tumor tolerance because of the up-regulation of heat shock protein(HSP)such as HSP-70.HSP-70 is a class of functional proteins with reversing or inhibiting denaturation of cellular proteins in reaction to hypoxic stress(PDT)or heat(PTT).Therefore,HSP-70 has been considered as the critical element in initiating the self-defense mechanism of tumors.For example,the temperature of over 50? is usually required to reverse the thermoresistance caused by HSP-70 for PTT.However,this high temperature may cause the damage of normal tissue near the tumor owing to the non-selective heat diffusion.Therefore,to inhibit the defense mechanism of tumors,the inhibitors suppressing the expression of HSP-70 should be combined in the same nanoplatform for reliable phototherapy.At the same time,we should also change the single treatment mode.This study attempts to combine PTT with chemotherapy to achieve synergistic anti-tumor effects.The toxic side effects of existing chemotherapy drugs have become the bottleneck of clinical treatment,so the development of a class of green and low-toxic anti-tumor drugs is imminent.The quercetin(Qu)discovered by researchers from natural products is not only a representative of naturally low-side effect anticancer drug but also a typical HSP-70 inhibitor for tailoring phototherapy.However,its clinical application is largely restricted by its unfavorable physicochemical and pharmacokinetic properties such as poor water solubility and bioavailability.Some efforts have been made on improving the water solubility of quercetin,including intravenous administration with dimethyl sulfoxide(DMSO)as a solvent and chemical modification.However,DMSO has serious side effects and bioavailability is only 20%via chemical modification strategy.Various encapsulating strategy has also been applied to improve water solubility of Qu,such as complexation with cyclodextrin or liposomal formulations.However,using cyclodextrin probably has the venture of renal toxicity,and instability during storage and low drug loading are usually occurred in case of liposomal formulations.Consequently,there is still an urgent demand to prepare a safety,stable and effective delivery platform that is able to solubilize Qu to meet intravenous administration.A growing number of nano-carriers have been applied to the co-delivery of photosensitizers and chemotherapeutic agents to tumor regions,allowing the synergistic therapeutic actions in an on-demand manner.However,the introduction of nano-carriers could result in the unknown side effects.Moreover,the conventional chemotherapeutic drugs usually have obvious side effects during treatment.Among the photosensitizers,IR780 is a structure analogue of FDA-approved photosensitizer indocyanine green(ICG),which has promising photothermal and photodynamic efficacy during phototherapy.However,its poor solubility in water largely restricted its clinical application.Based on the low side effects of quercetin with HSP-70 inhibition role and the excellent phototherapy ability of IR780,combination of Qu and IR780 in a therapy nanoplatform is principally promising for efficient and safe chemo-phototherapy.However,there is no report on the combination of Qu and IR780 for chemo-phototherapy up to date.This might be mainly because of the restriction of poor water solubility of both Qu and IR780,which makes their combination in one nanoplatform difficult for realizing satisfied drug loading and stable dispersions in water.Biotin is a water-soluble B vitamin that has a free carboxyl reactive group,also known as vitamin B7 or coenzyme R,with a simple chemical structure.The reactive group can be chemically bonded to the hydrophobic molecule to form an amphiphilic molecule,thereby improving the water solubility of the hydrophobic molecule.Moreover,biotin receptors are highly expressed on the surface of cancer cells,so it is often used as a superior tumor targeting molecule for targeted therapy against tumors.Herein,we firstly design a versatile chemo-phototherapy nanoplatform based on the combination of Qu and IR780.We used biotin as a hydrophilic tumor cell targeting unit to tailor IR780 for the formation of amphiphilic IR780 derivative(B780).The co-assembling of Qu and amphiphilic B780 in solution results in B780/Qu nanoparticles(B780/Qu NPs)with higher biosafety due to absence of additional carrier materials,successfully solving the problem of the poor solubility of quercetin and IR780.Moreover,the B780 was easier protonation in an acidic environment,largely improving its solubility and weakening hydrophobic interaction with Qu,which resulted in the nanoassembly disassembled.Therefore,our B780/Qu NPs are very promising as an efficient low side-effects and heat-shock protein-inhibited chemo-phototherapy nanoplatform against tumors.