Construction And Antitumor Activity Of Camptothecins Nano-drug Delivery System

Camptothecin(CPT)and 10-hydroxycamptothecin(HCPT)are quinoline alkaloids that isolated from the camptotheca acuminata of nyssaceae.As a kind of natural topoisomerase I(Topo I)inhibitor,CPT and HCPT have excellent therapeutic effect on a variety of tumors,and are most promising natural anticancer drugs in clinic.However,CPTs can not be directly applied to clinic due to the poor water solubility,short half-life in blood circulation,lack of targeting,and serious toxic side effects.Most currently developed CPTs derivatives and nanomedicines have not achieved the desired therapeutic effects due to the restriction of physiological barriers at various stages in the body.To solove these problems,in this work,a series of lignin-/cellulose-based CPTs delivery systems were designed and constructed with the aim of targeted delivery,long blood circulationtime,controlled drug release and drug synergistic therapy,and the antitumor activity was evaluated in detail.The main contents of this work as follows:(1)HCPT-loaded lignin-based targeted delivery system.Biopolymeric material lignin(AL)with good biocompatibility and biodegradability was used as a carrier to prepare lignin nanoparticles with uniform particle size and high drug loading capacity of HCPT by nano-precipitation method.Besides,in order to achieve the goals of long circulation in blood and tumor targeting,polyethylene glycol(PEG)and target molecule folic acid(FA)were introduced to lignin to prepare HCPT-loaded targeted nanoparticles(FA-PEG-AL/HCPT NPs).Compared with unmodified nanoparticles,the introduction of PEG chains significantly lengthened the blood circulation time of nanoparticles(-2.48 fold).The introduction of the targeting molecule FA increased the ellular uptake of tumor cells to nanoparticles by 2.21 times,achieving the goal of active targeting.In vivo biological distribution experiment showed that these targeted nanoparticles can significantly increase the retention and accumulation of HCPT in tumor tissues after tail vein administration.(2)Antibody-drug conjugate-based HCPT targeted delivery system.Antibody-mediated targeted drug delivery systems have attracted intense interests owe to the high sensibility and specificity of antibody.An amphipathic antibody-drug conjugate(MAPP)was prepared by using multiarm polyethylene glycol(PEG)as linker to couple monoclonal antibody(mAb)and hydrophobic drug pterostilbene(PS).HCPT-loaded targeted nanoparticles(MAPP/HCPT NPs)were prepared by self-assembly by using MAPP as carrier.The results showed that the prepared targeted nanoparticles had suitable particle size(?120.5 nm),higher drug loading(?24.2 wt%of HCPT)and longer blood circulation time(?8.7 fold of HCPT).In addition,such targeted nanoparticles can be specifically taken up by the tumor cells,achieving the goal of active targeting.Based on the above advantages,such targeted nanoparticles exhibit good antitumor activity and low toxic side effects in vivo and in vitro.(3)pH/GSH dual-responsive HCPT-loaded smart drug delivery system.Based on the unique weak acid and high concentration of reduced glutathione(GSH)environment of tumor tissue,constructing pH/GSH dual-responsive intelligent drug delivery system is expected to achieve the goal of drug release at selected location and a specific time.The hydrophobic drug molecule PS was coupled to the carboxymethyl cellulose(CMC)backbone by reducing dithiobispropion hydrazide(TPH)and multi-arm polyethylene glycol(PEG)as linkers to synthsis amphiphilic prodrug CMC-TPH-PEG-PS(CTPP).HCPT-loaded dual-responsive nanoparticles(CTPP/HCPT NPs)were prepared by using CTPP as carrier.In vitro release results showed that CTPP/HCPT NPs remained stable under normal physiological conditions,and the cumulative release of the drug was less than 20%within 72 h.On the contrast,these smart nanoparticles exhibited facilitated drug release begavior under weakly acidic(pH 5.0)and GSH(10 mM)environment with cumulative release of more than 70%of drug in 72 h.In vivo durg biodistribution experiments showed that these smart nanoparticles can significantly increase the drug concentration at the tumor tissue.(4)CPT and 131I co-delivey system.In the course of tumor treatment,long-term use of a single chemotherapy treatment strategy is prone to drug resistance,thereby resulting in limited therapeutic effects and serious side effects.Nanocarrier-based combination therapy strategy may provide an idea to solve this problem.BSA/CMC nanogel particles with uniform particle size were prepared using carboxymethyl cellulose(CMC)and bovine serum albumin(BSA)as carier materials through simple green self-assembly,achieving the goal of co-delivery of radiotherapy drug 131I and chemotherapy drug CPT.The results showed that the combination treatment group 131I-BSA/CMC-CPT nanogel particles displayed superior tumor inhibition effect and higher mice survival rate than single chemotherapy and radiotherapy,achieving the combined therapeutic effect.In summary,this wok constructed a series of multi-functional drug delivery systems for efficient delivery of CPT and HCPT,achieved excellent antitumor effects in vitro and in vivo.Meanwhile,these strategies can also provide reference and theoretical support for other natural anticancer drugs.