Controled Release Of Drug-loaded Micelles And Nanoparticles From Injectable Short Fibers

Nanocarriers can enhance the efficacy and reduce toxicity in the tumor treatment.According to the characteristics of tumor tissues and cells,intelligent nanocarriers with tumor targeting and stimuli-responsive drug release show a wide application prospect.In addition,local chemotherapy can increase the bioavailability,reduce the systemic drug toxicity,and improve the anti-tumor effect.Thus,this thesis designs several drug-loaded micelles and nanoparticles that targeted tumor cells and intracellular release of drugs,followed by loading in electrospun short fibers with acid sensitive properties.Prodrug-loaded micelles and hybrid micelles are designed by redox-reduction sensitive bond coupling with hydrophilic polymer and hydrophobic drugs,showing strong antitumor effect and low system toxicity.Tumor targeting and acid-sensitive nanomotors are designed to enhance the diffusion of nanoparticles in tissue tissues.Reduction-sensitive promicelles and nanomotors were chemically coupled or physical encapsulated in acid-labile injectable short fibers,and the sustained releases of micelles and nanomotors from short fibers result in significantly higher antitumor efficacy.Camptothecin(CPT)is conjugated on hylaronic acid(HA)through 3,3-dithiodipropionic to self-assemble into reduction-sensitive micelles(MC).The substitution degrees of CPT on HA backbone are tuned from around 4%-20%to clarify the effects on the cellular uptake efficiency and cytotoxicities of micelles,as well as the tumor accumulation and antitumor efficacy.The CPT substitution degree of around 15%on HA results in micelles with a higher cytotoxicity to 4T1 cells and achieves a better balance between the cellular uptake and reduction-triggered drug release,compared with other micelles.In contrast to an even distribution in major organs and a fast kidney clearance after intravenous injection of free CPT,the optimized micelles are preferentially accumulated in tumors,livers and lungs.The micelles accumulate in tumor tissues at about 4.9%,showing strong antitumor effect and low system toxicity.Furthermore,2-propionic-3-methylmaleic anhydride(CDM)is used to conjugate reduction-sensitive promicelle polymers and poly(DL-lactide)(PLA)to obtain acid-labile copolymers for the preparation of injectable short fibers.Short fibers show remarkable acid-sensitive degradation,and the released micelle carriers are spontaneously self-assembled into micelles,followed by CD44-mediated internalization into tumor cells and reduction-sensitive release of drugs in the cytosol.Compared to fresh micelles prepared by ultrasonication,the micelles released via the degradation of fiber fragments display similar behaviors,such as the size and morphology,glutathione-sensitive drug release,cellular uptake efficiency,and cytotoxicity.Compared to the intratumoral injection of free micelles,the sustained micelle release from short fibers results in significantly higher antitumor efficacy.a-Tocopherylsuccinate(TOS)is decorated with cationic triphenylphosphonium(TPP)to promote the targeting capabilities of TOS-TPP to mitochondria.The combination of CPT and TOS-TPP shows strong synergistism with a combination index(CI)of 0.169.CPT and TOS-TPP are conjugated with HA via disulfide linkages as micelle carriers(MC and MT-P)for tumor cell targeting,and MC/T-P hybrid micelles are prepared from their blends at different ratios.In response to the elevated intracellular glutathione levels,the coordinate releases of CPT and TOS-TPP from MC/T-P shows a CI of 0.203 and the dose-reduction indices of CPT and TOS are 10.5 and 5.8,respectively,at the predetermined synergistic ratio of CPT/TOS at 1/2.Compared with MC and MT-P,MC/T-P micelles with 5 folds lower doses produce higher intracellular reactive oxygen species(ROS)levels and comparable tumor growth inhibition and animal survival extension while indicating no hematologic and intestinal toxicities.The MC/T-P micelle carriers with conjugated with polylactide via acid-labile linkers for construction of short fibers(MC/T-P@SF)as an implantable depot for micelle releasing in response to the acidic tumor microenvironment.At the predetermined synergistic ratio,MC/T-P@SF short fibers shows a CI of 0.376 and the treatment with 5 folds lower doses achieves similar antitumor profiles comparable to those of individual micelles-loaded short fibers with respect to the tumor growth inhibition,animal survival,and histological staining of tumors retrieved.Therefore,this study suggests a feasible strategy to achieve a synergistic treatment efficacy of hybrid micelles and micelles-releasing short fibers.Hydroxyapatite nanoparticles are coated with mesoporous silica(MSN)shell,followed by physical vapor deposition of gold layer to prepared Janus nanoparticles.HA and urease are conjugated separately on the Janus nanoparticles to obtain Janus nanomotors(JNM).JNMs are loaded in injectable short fibers to achieve a sustainable release of JNMs in tumor microenvironment,and the presence of urea propells JNMs to improve the penetration and distribution in the tumor tissue.JNMs enter tumor cells via the receptor mediated endocytosis and release Ca2+,and CPT enters cytoplasma after endosomal escape to induce cell apoptosis.The acid-labile and sustained release of JNMs and the self-propelled and targeting capabilities of JNMs could effectively overcome the effect of tissue macromolecular crowding environment on the diffusion of nanoparticles,improve the permeate of nanoparticle and enhance the antitumor effect.In this thesis,drug-loaded micelles and JNMs with stimuli-responsiveness and tumor targeting capabilities are developed,followed by loading into acid-labile short fibers for intratumor administration.The design offers the local release of micelles or nanoparticles form short fibers,the efficiecnt distribution in the tumor tissues,the HA-mediated tumor cell uotake and stimuli-responsive intracellular drug release,demonstrating a feasible strategy to enhance the anti-tumor effect and reduce the systemic toxicity.