Multistage Nanoparticulate Drug Delivery System For Cancer Therapy

Nanoparticle-based drug delivery systems show great promise for enhanced anticancer therapy.However,cancer nanomedicine encounters a series of biologic barriers in vivo,including blood barrier,tumor tissue barrier and tumor cell barrier.How to collaboratively tune the characteristics of nanomedicine to overcome the multiple biologic barriers for efficient drug delivery is still facing numerous challenges.In this dissertation,we focus on the development of multistage clustered nanomedicine to systematically overcome these multiple barriers of cancer chemotherapy.The main content of this dissertation is described in two parts as below:1.We developed stimuli-responsive clustered nanoparticles to systematically overcome these multiple biologic barriers to cancer chemotherapy.The nanoparticles were constructed through molecular assembly of platinum(Pt)prodrug-conjugated tumor acidic microenvironment responsive poly(amidoamine)-graft-polycaprolactone(PCL-CDM-PAMAM/Pt))with polycaprolactone(PCL)homopolymer and poly(ethylene glycol)-b-poly(c-caprolactone)(PEG-b-PCL)copolymer.PEG-b-PCL is employed to offer stealth layer,while PCL is chosen to control the size and stability.The nanoparticles are able to function adaptively in the body through precisely responding to the physiological pH,tumor extracellular acidity,and intracellular reductive environment,respectively.At physiological pH,the clustered nanoparticles hold the size around 100 nm,and have high propensity of long blood circulation and enhanced tumor accumulation through the EPR effect.Then,the acidic tumor extracellular pH(pHe,?6.5—7.2)triggers the release of small PAMAM prodrugs(?5 nm),which enable to execute deep and uniform tumor penetration to reach more cancer cells.Finally,the PAMAM prodrugs can be rapidly reduced in the reductive cytosol to release active and potent cisplatin to kill cancer cells and lead to robust antitumor efficacy.2.We developed ultra pH-sensitive clustered nanoparticles(SCNs)for improved tumor penetration of nanoparticle and drug delivery efficiency.The platinum(Pt)-prodrug conjugated SCNs(SCNs/Pt)are self-assembled from poly(ethylene glycol)-b-poly(2-azepane ethyl methacrylate)-modified PAMAM dendrimers(PEG-b-PAEMA-PAMAM/Pt).At neutral pH,PAEMA is hydrophobic and directs the assembly of PEG-b-PAEMA-PAMAM/Pt into SCNs/Pt(?80 nm in diameter)for prolonged blood circulation,meanwhile,this nanoparticle show excellent stability in blood environment,while at acidic tumor pH,the PAEMA is rapidly protonated and transformed to hydrophilic,leading to instantaneous disintegration of SCNs/Pt into small nanoparticles for effective tumor penetration,what's more,this nanoparticle perform a dramatic and sharp size transition within a very narrow range of acidity(less than 0.1-0.2 pH units).This rapid size-switching feature can not only facilitate nanoparticle extravasation and accumulation via the enhanced permeability and retention(EPR)effect,but also allows faster nanoparticle diffusion and more efficient tumor penetration.