Design,Preparation And Evaluation Of Small Molecular Based Nanodrug For Cancer Therapy

Nanodrug has shown great advantages in improving the therapeutic effect and reducing side effects,which opens a new window for cancer therapy.Recently,a novel nanodrug delivery system,small molecule based nanodrug(SMND),has emerged.SMND is a type of self-carried nanodrug,whose nanoparticles(NPs)are mainly composed of small molecules with or without a little material as stabilizer.It has attracted great interest as a desirable strategy,because of its unique properties in increased chemical stability and solubility,high drug load,economical fabrication,relative "green" nanoformulation,without a large amount of polymer etc.This study first reviewed the progress and design strategies of SMND.On these foundations,three types of SMND were designed to overcome the problem of chemotherapy drugs in clinical application and reveal the relationship between self-assembly behavior and molecular structure.This study would provide a theoretical basis for the reasonable design of SMND and promote the wide application and development of SMND.The main contents are as follows:Chapter 1.Disulfide induced self-assembled nanodrug of SAHA.Vorinostat(SAHA)is a canonical FDA-approved histone deacetylase(HDAC)inhibitor for the treatment of cutaneous T-cell lymphoma.However,the lack of efficacy against solid tumors is hindering its progress in clinic.Herein,a novel nanodrug of SAHA was developed based on disulfide-linked conjugate SAHA-S-S-VE.SAHA-S-S-VE could self-assemble into 148 nm NPs by disulfide-induced mechanisms,which were validated by molecular dynamics(MD)simulations.Under reduced conditions,the redox responsive behavior of SAHA-S-S-VE was investigated,and the HDAC inhibition results verified the efficient release of free SAHA.With a biocompatible D-a-tocopheryl polyethylene glycol succinate(TPGS)functionalization,the SAHA-S-S-VE/TPGS NPs exhibited low critical aggregation concentration 4.5 ?M and outstanding stability in vitro with drug loading capacity 24%.In vitro biological assessment indicated SAHA-S-S-VE/TPGS NPs had significant anticancer activity against HepG2.Further in vivo evaluation demonstrated that the resulting NPs could be accumulated in tumor region and inhibited the tumor growth effectively.This approach that turned SAHA into self-assembled redox responsive nanodrug provided a new channel for the use of HDAC inhibitor in solid tumor therapy.Chapter 2.Amphiphilic self-assembled complex nanodrug of SAHA/5-Fu.Combination chemotherapy has shown great promise in cancer treatment,and the nanoscale co-delivery system is helping to pave the way.However,there still exists a formidable challenge to co-delivery multi-drugs with precise and ratio tunable load,thereby enabling dosage optimization.Herein,we reported a novel co-delivery system,complexed small molecule based nanodrug(Co-SMND),of which two different conjugates co-assembled into a single nanoparticle with ratiometric drug load.To demonstrate this approach,drug-lipid conjugates(5-Fu-VE and SAHA-VE)were synthesized through coupling 5-fluorouracil(5-Fu)and vorinostat(SAHA)with an auxiliary lipophilic segment(D-a-Tocopherol succinate,VECOOH),respectively.Taking advantage of the hydroxyl or amino groups in drugs as hydrophilic moiety,5-Fu-VE and SAHA-VE were endowed with amphiphilicity to form NPs without any carriers.After various ratios of conjugates were dispersed in water,all samples formed spherical NPs with nanometer size(80 to 190 nm)and uniform size distribution.Hydrolytic assay indicated Co-SMND could achieve on-demand hydrolysis and destruction responding to pH stimuli in tumor cell.Importantly,in vitro biological assay confirmed that the maximum synergistic effect of Co-SMND could be achieved via simply adjusting the molar ratio of conjugates,and the Co-SMND induced a much higher apoptosis rate than single one.Further in vivo studies demonstrated that the optimized Co-SMND possessed superior antitumor efficacy(p<0.05)and reduced toxicity to cocktail therapy,which correlated well with its selective intratumoral accumulation(p<0.001).This co-delivery strategy provided a simple and precisely controlled approach for combination therapy.Such a highly reproducible system could be widely applied to co-deliver other various drugs,as well as three or more drugs,for combination therapy.Chapter 3.D-a-Tocopherol succinate induces sorafenib(SF)into nanosuspensions(NS).Prepare nanodrug of anti-cancer agents based on the interaction between heterogeneous molecular-molecular,using a little amphiphilic molecule as stabilizer,which is to be a more green and environmentally friendly method.However,little is known about how to choose a suitable stabilizer and the related "structure and activity relationship".SF was chosen as a model drug,due to its low water solubility and low oral bioavailability,which limit its clinical application.10 small molecules were chosen as stabilizers.SF was prone to co-assemble with VECOONa(8)to form NS,after screening through the stability of the formulation.The resulting SF NS showed round appearance,uniform particle size(about 90 nm)and high drug load 46%.The UV absorption and X ray powder diffraction of SF NS indicated that SF formed NS by the induction of intermolecular interaction.In addition,MD simulation and Quantum Chemistry Computation were first introduced to study the co-assemble mechanism and structure-activity relationship.In vitro release experiment showed that SF NS have an equivalent release rate to free SF drug,and significantly higher than that of SF suspension,which confirmed that SF might distribute in an amorphous state.In vitro anti-proliferative results showed that SF NS had an equivalent IC50 with free drug toward HepG2 cells.In vivo pharmacokinetics results indicated that the AUC0-24 of SF NS was 2-fold than that of SF solution(i.v.),and 40-fold than that of SF suspension(p.o.).Further in vivo evaluation demonstrated that SF NS could significantly inhibit the tumor growth effectively compared with SF solution(p<0.01),and showed no significant off-target toxicities to major organs and tissues.