Design And Preparation Of Nano Drug With Targeting Tumor Cell Mitochondrial Transmission Co Property And Its Anti-cancer Performance Research

Chemotherapy and radiotherapy are commonly used as first-line treatment methods of cancer treatment in the international medical community.However,most of the existing chemical/radiation therapeatie agents have non-specific toxicity to normal tissues and blood.The development of novel anticancer drugs with high efficiency,low toxicity and novel mechanism of action have attracted much attention in the field of drug research and development.Fortunately,it is discovered that some gaseous signaling molecules such as CO and NO can selectively induce apoptosis of cancer cells and protect normal cells at appropriate concentrations.This anti-cancer selectivity of gas therapy is clearly superior to traditional chemotherapeutic/radiotherapeutic drugs.Thus,gas therapy is emerging as a promising treatment strategy.CO has small molecular weight and high transmembrane diffusivity,but this diffusion is aimless.If a large amount of CO diffuses into the blood,it will bring potential risk of blood poisoning;If the concentration of CO is too low,its bioavailability will be low and its drug efficacy will be limited.In the current clinical practice of gas therapy,two main CO administration routs are direct inhalation of CO gas and uptake of CO prodrugs.It is difficult to control the dose of CO intake by direct inhalation of CO gas,while existing prodrugs lack the ability of tumor targeting.Both routes of administration may result in a high risk of carbon monoxide poisoning.It is an important strategy to construct a new targeted nano-drug delivery system by integrating advanced nano-materials,CO prodrugs targeting tumors and intelligent nano-drugs controlled release of CO in tumors.Some nanomedicines have been developed for tumor-targeted and controlled release of CO,but they can only release CO into lysosomes or cytoplasm rather than mitochondria.It is well known that mitochondria are the target for CO to exert its physiological functions.CO can inhibit mitochondrial respiration by competing with oxygen to bind cytochrome C oxidase in the body,damage the mitochondrial bioenergy of tumor cells,and lead to tumor cell apoptosis.Therefore,we also hypothesize that the multistage targeting of CO prodrugs to the tumor tissue-cell-mitochondria may obtain the ideal gas therapeutic effect.In this work,we propose a novel multistage assembly/disassembly strategy and construct a versatile intelligent nanomedicine(Fe CO-TPP@MSN@HA).The intramitochondrial microenvironment-responsive prodrug(Fe CO-TPP)prodrug was prepared by ligand-exchange reaction of Fe3(CO)12 and TPP-SH.Fe CO-TPP can be effectively targeted to the mitochondria for cancer therapy.The Fe CO-TPP prodrug was loaded into MSN to achieve passive tumor targeted drug delivery of tumor tissue through enhanced permeability and retention effect.Further coating of hyaluronic acid(HA)on the surface of small-sized MSN(Fe CO-TPP@MSN@HA)by electrostatic assembly achieves both passive tumor targeting and active targeting to CD44-overexpressed tumor cells.The targeted drug delivery can realize the tumor tissuetargeted delivery of the nanomedicine(first-step targeting),the tumor cell-targeted delivery of the nanomedicine(second-step targeting),the acid-responsive release of a new CO prodrug from the nanomedicine(first-step controlled release),the mitochondria-targeted delivery of the prodrug(third-step targeting),and the intramitochondrial ROS-responsive release of CO(second-step controlled release).Fluorescence colocalization in vitro verified the targeted drug delivery and subsequent prodrug/CO triggered release of the tumor tissue–tumor cells–mitochondria.Cellular energy metabolism showed that nanomedicines enhanced the damage to mitochondrial function in cancer cells and protected the mitochondrial function of normal cells to maintain normal energy metabolism.In vivo tumor mice results showed that Fe COTPP@MSN@HA nanoparticle could significantly inhibit tumor growth and metastasis.In a word,these results suggest that our proposed multistage assembly/disassembly strategy provides a new approach for the design of nanomedicine.