Preparation And Antitumor Study Of Human Serum Albumin-Hyaluronic Acid Nanoparticles

Cancer is one of the leading causes of human mortality worldwide,and it has the characteristics of high incidence,severe symptoms and poor prognosis.Traditional treatments for cancer include radiation therapy,surgical excision,and chemotherapy.Since chemotherapy drugs with highly toxic to cells are easily cleared and have large side effects when used alone,the selection of an efficient drug delivery system is expected to achieve precise treatment of tumors.The drug delivery system can not only control the release of chemotherapy drugs,but also effectively improve the stability and circulation time of drugs in vivo,so as to realize the purpose of precision treatment of tumors.Human serum albumin(HSA)is widely used in the delivery and bioimaging of small molecule therapeutic drugs as an endogenous protein which exhibits minimal biotoxicity and immunogenicity.Among them,due to the presence of reactive residue amine groups and carboxyl groups,HSA is also suitable for chemical modification to covalently bind targeted ligands,so that the nanodrug delivery system can not only enter the tumor area through enhanced penetration and retention(EPR)effects,but also actively target tumor cells.As one of the best-selling FDA-approved cancer drugs,HSA-paclitaxel(PTX)nanoparticle(Abraxane)exhibits similar disadvantages to most chemotherapy drugs,that is,it produces strong side effects at high doses and leads to drug resistance.Indocyanine green(ICG),an FDA-approved near-infrared fluorescence dye with photothermal(PTT)and photodynamic(PDT)properties,can be combined with HSA to prepare HSA-ICGPTX nanoparticles based on self-assembly strategy,showing obvious synergistic effects.However,HSA-ICG-PTX nanoparticles will inevitably be ingested by normal cells,and the development of nanoparticles that can be specifically ingested by tumor cells has become a new way to solve this problem.Hyaluronic acid(HA),a high molecular weight linear glycosaminoglycan,can be specifically targeted to CD44 receptors on the surface of tumor cells.This study constructs a HA-functionalized nanodrug delivery system(HSA-ICG-PTX@HA).HSA,ICG and PTX are self-assembled into HSA-ICG-PTX nanoparticles.Under alkaline conditions,HSA-ICG-PTX@HA nanoparticles were prepared by covalently binding HSA-ICG-PTX nanoparticles to HA by amidation reaction.Due to the surface of tumor cells overexpressed CD44 receptors,HSA-ICG-PTX@HA nanoparticles will autonomously target tumor cells,thereby reducing drug enrichment of other normal organs.Experimental results such as ultraviolet-visible-near-infrared absorption spectroscopy,particle size,and ζ potential showed the successful preparation of HSAICG-PTX@HA.The results of in vitro PTT and PDT experiments and cytotoxicity experimental results showed that HSA-ICG-PTX@HA exhibited good PTT and PDT effects,as well as significant targeting capacity.Meanwhile,the results of the cell flow cytometry test showed that the combination chemotherapy-photothermal-photodynamic therapy induces apoptosis and necrosis of He La cells and MCF-7 cells.The results of in vivo anti-tumor experiments demonstrated that compared with HSA-ICG-PTX,HSAICG-PTX@HA has better enrichment ability and enhanced photothermal effect in tumor tissue and showed good anti-tumor efficacy.Therefore,this study has successfully constructed a biocompatible nanodrug delivery platform composed entirely of FDAapproved compounds,which is expected to be used for fluorescence/photothermal imaging-mediated combination chemotherapy-photothermal-photodynamic combination therapy in the future.