Design And Fabrication Of Intelligent Drug Delivery Systems For Tumor Targated Therapy

Nowadays,cancer has become one of the most threatening diseases to human health because it was hard to cure,easy to metastasis and relapse with high mortality.So far,cancer therapy still relies principally on the surgical removal,chemotherapy,and radiotherapy.Traditional chemotherapeutics have many defects,such as poor water-solubility and non-selectivity,causing the high toxicity,low bioavailability and therapeutic effect.Thus,researches have designed a lot of multifunctional smart drug delivery systems for efficient tumor targeted therapy with minimized side effects.Moreover,inspired by the various biological functions in nature,researches have devoted themselves to modify the nanocarriers for biology simulation by using the biomimetic strategy.As a result,this biomimetic functionalization would improve the biocompatibility and tumor targeting ability of nanocarriers for maximizing the therapeutic effect.Based on these,we constructed a series of multifunctional drug delivery systems to adapt the tumor microenvironments for tumor targeted therapy.The detail is displayed as follow:In chapter one,we made a brief description to the currently available tumor targeting strategies,especially for designing stimuli-responsive drug delivery systems by utilizing tumor microenvironments.Besides,the burgeoning concept of bionics was introduced.Particularly,the construction of biomimetic nanoplatforms for tumor therapy on the basis of natural membrane was also described in detail.In chapter two,an acid-responsive peptidic prodrug was designed for tumor targeted therapy.In briefly,the prodrug was constructed by conjugating the antitumor drug doxorubicin(DOX)to an activable cell-penetrating peptide(CR8G3PK6,ACPP)with a shielding group of 2,3-dimethylmaleic anhydride(DMA).The shielding group of DMA linked to the primary amines of K6 through the amide bond was used to block the cell-penetrating function of the polycationic CPP(R8)through intramolecular electrostatic attraction at physiological pH 7.4.At tumor extracellular pH 6.8,the hydrolysis of DMA led to charge reversal,activating the pristine function of CPP for improved cellular uptake by tumor cells to achieve the tumor targeted therapy.In chapter three,the concept of ACPP was still utilized to construct a conjugate of matrix metalloproteinases-2(MMP-2)-sensitive activable cell-penetrating peptide(RgGPLGLAGE8,ACPP)with protoporphyrin(PpIX)for tumor targeted photodynamic therapy(PDT).The ACPP was composed of a polycationic CPP(R9),an MMP-2-sensitive oligopeptide(GPLGLAG),and a polyanionic peptide(E8).In normal tissue,the cell-penetrating function of polycationic CPP(R9)would be blocked by a polyanionic peptide(E8)through intramolecular electrostatic attraction,which was beneficial to prolong the blood circulation time and lower side effects.Once exposed to MMP-2 existing at the tumor site,proteolysis.of the oligopeptide linker would activate the cell-penetrating function of CPP-PpIX for tumor targeted PDT.In chapter four,an O2 self-sufficient cell-like biomimetic nanoplatform was developed for tumor targeted PDT.This cell-like biomimetic nanoplatform(CAT-PS-ZIF@Mem)was composed of the cancer cell membrane(Mem)and a cytoskeleton-like porous zeolitic imidazolate framework(ZIF-8)with the embedded catalase(CAT)molecules and Al(III)phthalo-cyanine chloride tetrasulfonic acid(AlPcS4,defined as PS).This biomimetic nanoplatform(CAT-PS-ZIF@Mem)would present source cell specific targeting because it had the same cell adhesion molecules as the cancer cells.What's more,it allowed tumor-associated antigen and immunological adjuvant to induce immune escape.After intravenous injection,CAT-PS-ZIF@Mem could achieve the tumor preferential accumulation and uptake.Subsequently,the high level of intracellular H2O2 was catalyzed by CAT to produce O2 at the hypoxic tumor site,improving the therapeutic effect of PDT.This integrating utilization of biomimetic cell membrane-coating technique and O2 self-sufficiency greatly enhanced PDT selectivity and the therapeutic effect in hypoxic tumor tissue with much reduced side-effect on normal tissues.In chapter five,a cancer cell membrane-coated biomimetic nanoplatform(TPZ@PCN@Mem)was designed for tumor targeted combination therapy.TPZ@PCN@Mem was fabricated by loading bioreductive drug tirapazamine(TPZ)in porphyrinic metal organic framework PCN-224 and then coating with the homotypic cancer cell membranes.After intravenous injection,TPZ@PCN@Mem was possessed of the immune evasion and source cell specific targeting ability for selectively tumor accumulation and cellular uptake.Afterwards,PCN-224 in the nanoplatform would be excited to produce cytotoxic ROS under light irradiation for PDT.In addition,the photochemical oxygen consumption induced hypoxic aggravation would further facilitate the activation of TPZ for successive bioreductive chemotherapy.By both in vitro and in vivo investigations,this excellently homologous targeting as well as the robustly synergistic therapeutic effect of TPZ@PCN@Mem exhibited efficient primary tumor therapy and successful metastasis suppression.