Construction Of Nano-composite Materials And Their Antitumor And Wound Healing Performance

Among the developed and utilized nanomaterials,nanoparticles and electrospun nanofibers have shown great potential in many biomedical applications including cancer therapy,drug delivery and wound healing owing to their unique inherent properties and functions.Aiming at some practical problems existing in cancer treatment and wound repair,this thesis has designed and prepared a series of multifunctional composite nanomaterials by using nanoparticles and electrospun nanofibers as drug delivery carrier.Meanwhile,we respectively explored its application potential in cancer treatment and enhanced wound healing.The main research contents are included as follows:1.Hyaluronic acid modified selenium nanoparticles loaded with ICG for highly effective chemophotothermal combination tumor therapyA combination of chemotherapy and photothermal therapy has already become a promising strategy for cancer treatment.In this study,we have successfully developed a CS-Se/HA@ICG composite nanoplatform by covalently grafting hyaluronic acid（HA）on the surface of chitosan coated Se nanoparticles（SeNPs）and subsequently loaded with ICG.The nanosystem could deliver SeNPs（chemotherapeutic agents）and ICG（photothermal agents）precisely to the tumor area simultaneously for combined chemo-photothermal therapy.HA shell had the capacity for extending blood circulation and could enhance the tumor-specific accumulation of composite nanoparticles via CD44-mediated pathway.After targeting into cancer cells,HA shell would be disintegrated by hyaluronidase in the tumor microenvironment,and thus leading to the release of ICG.The study verified that the nanodelivery system significantly enhanced the photothermal stability of ICG and displayed a higher temperature response than the free ICG under laser irradiation.The combined therapy offered by the CS-Se/HA@ICG with laser irradiation enhanced anticancer properties compared with SeNPs alone.ICG would produce both light heat and singlet oxygen under near infrared laser（808 nm）irradiation,which could synergically trigger intracellular reactive oxygen species（ROS）overproduction with SeNPs,inducing the decrease of mitochondrial membrane potential,and thus leading to tumor cell apoptosis.2.Mesoporous polydopamine nanoplatforms loaded with calcium ascorbate for amplified oxidation and photothermal combination tumor therapyInducing apoptosis of cancer cells by selectively increasing oxidative stress in tumor tissue has been proved to be an efficient tumor therapeutic approach.However,elevated antioxidant defense systems in cancer cells result in resistance to the therapy involving ROS.Herein,a smart nanoplatform based on calcium ascorbate（Vc-Ca）loaded MpDA was firstly designed and prepared for amplified oxidation and photothermal combination therapy,through ROS self-generation,regulation of redox homeostasis and hyperthermia.Typically,Vc-Ca was encapsulated within MpDA by a phase change material（PCM）under physiological conditions（approximately 37℃）.Upon irradiation by a NIR,the PCM was melted due to the photothermal effect of MpDA,leading to the release of Vc-Ca to selectively generate H₂O₂ in tumor site.Remarkably,MpDA could eliminate the endogenous ROS scavenging system through depleting the primary antioxidant,thus amplifying Vc-Ca-mediated oxidative therapy.The multifunctional nanoplatform combined with laser irradiation exhibited remarkable hyperthermia and enhanced ROS synergistic therapy efficiency,which significantly inhibited tumor growth in vitro and in vivo.3.Copper-based metal-organic framework loaded calcium ascorbate through H₂O₂ self-supplying and GSH-depletion for enhanced chemodynamic therapyChemodynamic therapy（CDT）employs Fenton catalysts to kill cancer cells by converting intracellular H₂O₂ into hydroxyl radical（·OH）,but the insufficient of endogenous H₂O₂ severely limits its anticancer efficacy.Despite tremendous efforts,engineering CDT agents with specific and efficient H₂O₂ self-supplying ability remains a great challenge.Here,we have reported a novel chemodynamic nanosystem for enhanced CDT by self-generation H₂O₂ and GSH depletion.Vc-Ca,serving as an original source for H₂O₂ generation,was loaded on the surface of Cu²⁺-doped ZIF-8（Cu/ZIF-8）and subsequently coated with HA to form the Cu/ZIF-8/Vc-Ca/HA composite nanosystem.The nanosystem could specifically accumulate in tumor cells through CD44-mediated active targeting and EPR effects.After endocytosis into tumor cells,acidic environment of endo/lysosomes accelerated the dissociation of Cu/ZIF-8/HA@Vc-Ca,allowing slow release of Vc-Ca and Cu²⁺.Vc-Ca could induce H₂O₂ production in tumor cells,which provided abundant H₂O₂ for subsequent Fenton-like reaction.Moreover,the released Cu²⁺would react with local GSH,lead to GSH depletion,and the byproduct Cu+could further induce CDT process and undergo highly efficient Fenton-like reaction to generate high content of toxic·OH.Biological assays indicated that Cu/ZIF-8/HA@Vc-Ca presented significantly improved anti-tumor effect by enhancing CDT compared with Cu/ZIF-8 or Vc-Ca alone.4.Polydopamine-assisted decoration of Se nanoparticles on curcumin-incorporated nanofiber matrices for localized synergistic tumor-wound therapyThe management of surgical wounds incurred during tumor removal procedure has become a nonnegligible issue.Herein,for the first time,an implantable polymer-based nanofiber matrix was developed for postoperative tumor management by promoting wound healing and preventing cancer recurrence.The multifunctional matrix was successfully prepared by assembling chitosan-stabilized SeNPs at the surface of polydopamine（PDA）modified poly（ε-caprolactone）/curcumin fibres（PCL/CUR）,denoted as PCL/CUR/PDA@Se.In this system,PDA as functionalized layers coated onto PCL/CUR surface favored the effective immobilization of SeNPs through covalent bond,as well as acted as gatekeeper guaranteeing the sustained release of CUR.The CUR/SeNPs presented excellent antitumor efficacy,respectively,which supported the nanocomposite matrix to efficiently kill cancer cells in vitro by inducing mitochondrial dysfunction caused by the ROS overproduction,and significantly suppressed the tumor growth in vivo.Additionally,due to the synergistic antioxidant activity of CUR and SeNPs,the nanofibrous matrix distinctly facilitated the adhesion and proliferation of normal fibroblast cells,and simultaneously accelerated wound healing during tumor treatments in tumor-bearing mice.5.Chlorogenic acid assist dopamine-sodium alginate composite nanofiber membranes to have enhanced antioxidant activity for wound healingDeveloping safe and effective new antioxidant bioactive dressings to enhance full-thickness skin wound regeneration is highly desirable in clinical application.In this study,we proposed to using chlorogenic acid（CA）as a component of regenerative wound dressing,and for the first time,introduced it into dopamine-functionalized sodium alginate（Alg-DA）conjugates,and utilizing polyvinyl alcohol（PVA）as carrier polymer to develop a series of biocompatible antioxidative and angiogenic composite nanofiber membranes（PVA/Alg-DA/CA）for wound dressing.Free radical scavenging tests demonstrated that PVA/Alg-DA/CA composite membranes had excellent antioxidant properties.The ROS scavenging ability of the composite nanofiber membranes could protecte cells from oxidative damage under oxidative stress conditions.Based on the advantages of nanofiber structure and the biofunctional activities of CA and Alg-DA,PVA/Alg-DA/CA composite membranes exhibited excellent biocompatibility and effectively supported the adhesion and proliferation of fibroblasts.In addition,wound closure and histopathological analysis showed that PVA/Alg-DA/CA composite membranes could promote neovascularization and tissue remodeling,and thus accelerating wound closure in the mouse full-thickness wound defect model.Meanwhile,these multifunctional membranes accelerated wound healing by upregulating the expressions of CD31 and TGF-β1 protein.