Construction Of Tumor Targeting Theranostic Drug Delivery Systems

Construction of tumor targeted drug delivery systems would extensively improve the therapeutic efficiency of traditional anti-cancer agents.However,the complicated cancer microenvironment as well as the individual diversity would lead to the failure of standardized treatment.To meet the impending demands for precise cancer treatment,it is urgently needed to construct multi-functional theranostic systems for simultaneous cancer targeting drug delivery,cancer imaging,cancer diagnosis and prognosis.Traditionally,drug carriers could be actively delivered into cancer cells by conjugating small-molecular ligands or passively transferred to cancer tissues by enhanced permeability and retention(EPR)effects.Moreover,inspired by the unique homotypic behavior of immune cells and the immune escape nature of cancer cells,it is advantageous to construct theranostic systems by biomimetic functionalization of the drug carriers or even employing the natural cells as cell vehicles.Meanwhile,the intracellular drug distribution and drug release as well as the signal translations along with cancer treatment(such as therapeutic response and therapeutic efficacy evaluation)could be noninvasively monitored by using F6rster Resonance Energy Transfer(FRET)imaging techniques.Finally,the cancer therapeutic strategies,therapeutic dosages and the therapeutic processes could be optimized according to the personalized requirements.In Chapter 1,the strategies for cancer targeting delivery and dynamic therapeutic processes monitoring is introduced,and the progress of cancer targeted theranostic drug delivery systems have reviewed.In chapter 2,a cancer cell targeted theranostic prodrug FAM-GC(Mal-hyd-DOX)SDEVDSK(Dabcyl)RGD,short as V-Prodrug)had been constructed for cancer targeted therapy,drug release monitoring and therapeutic efficacy evaluation.The fluorescence of 5(6)-carboxyfluorescein(FAM)and hydrozone bond linked doxorubicin(DOX)was quenched by 4-(dimethylaminoazo)benzene-4-carboxylic acid through dual-FRET processes.Due to the RGD targeting moiety,V-Prodrug could selectively accumulate in ?v?3 integrin overexpressed cancer cells.Subsequently,the acid intracellular microenvironment could accelerate DOX release from V-Prodrug,and its fluorescence recovery could be used for DOX release monitoring.Moreover,DOX-induced cell apoptosis can also be in situ assessed by the fluorescence recovery of the FAM,due to the caspase-3-mediated Asp-Glu-Val-Asp(DEVD)peptide sequence cleavage in V-Prodrug.And the early therapeutic response and the anti-cancer efficacy could be in situ evaluated noninvasively.In chapter 3,a ratiometric theranostic probe(FAM-K(PpIX)SDEVDSK(Dabcyl)RGD,short as P-PpIX)was fabricated for cell apoptosis imaging,cancer cell targeted PDT and therapeutic efficacy evaluation.The Arg-Gly-Asp(RGD)targeting moiety endowed P-PpIX to selectively accumulate in ?v?3 integrin overexpressed cancer cells.Upon photo irradiation,the PDT effect of P-PpIX could induce cell death with apoptosis related mechanism,and the activated caspase-3 would subsequently cleave the Asp-Glu-Val-Asp(DEVD)peptide sequence to terminate the intramolecular FRET process.The activated caspase-3 expression and the real time therapeutic efficacy could be precisely assessed in situ by the fluorescence intensity ratio of the released 5(6)-carboxylfluorescein(FAM,reporter fluorescence)and protoporphyrin ?(PpIX,internal reference fluorescence).In chapter 4,a cancer targeted cascade bioreactor(designated as mCGP)was constructed for synergistic starvation and photodynamic therapy(PDT)by embedding the glucose oxidase(GOx)and catalase in the cancer cell membrane-camouflaged porphyrin metal organic frameworks(MOFs)of PCN-224(PCN stands for porous coordination network).Due to the biomimetic surface functionalization,the immune escape and homotypic targeting behaviors of mCGP would dramatically enhance the cancer targeting and retention abilities.Once internalized by cancer cells,mCGP was found to promote the microenvironmental oxygenation by catalyzing the endogenous H2O2 to produce O2,which would subsequently accelerate the decomposition of intracellular glucose and enhance the production of cytotoxic singlet oxygen(1O2)under light irradiation.Consequently,mCGP displayed amplified synergistic therapeutic effects of long-term cancer starvation therapy and robust PDT,which would efficiently inhibit the cancer growth after a single administration.In chapter 5,a versatile plasma membrane engineering approach was constructed for cancer targeting drug delivery and therapy by anchoring functionalized conjugates to natural cells.The membrane anchoring amphiphilic conjugates were comprised of a positively charged tetra-arginine peptide sequence,a palmitic-acid-based membrane insertion moiety,and a lysine linker whose s-amine was modifid with camptothecin(CPT),protoporphyrin IX(PpIX),or florescein(FAM).The amphipathic CPT,PpIX,or FAM conjugates(short as aCPT,aPpIX,or aFAM,respectively)could easily and steadily anchor or coanchor on the cell membrane of RAW264.7 cells(short as RCs),red blood cells(RBCs),or mesenchymal stem cells(MSCs).After anchoring aPpIX in RC cells,the cancer targeting ability and therapeutic effect of aPpIX-anchored RC cells(short as aPRCs)is demonstrated in vitro and in vivo.Due to the good cancer-targeting ability,aPRCs can effiiently inhibit the cancer growth with no systemic toxicity after photoirradiation by photodynamic therapy.