Polydopamine Based Hybrid Mesoporous Microporous Nano-drug Carriers And The Biological Application

Multidrug resistance?MDR?is the main mechanism for the resistance of cancers to chemotherapeutic drugs,and it is also one of the main obstacles to the successful treatment of various cancers.Mesoporous silica nanoparticles?MSNs?with high specific surface area provide an opportunity for the delivery of chemotherapeutic drugs.However,there are still some problems need to be solved in reversing MDR:?1?low drug loading;?2?uncontrollable drug loading and release;and?3?the biological security of nanomaterials.Therefore,it is urgently to find specific materials that have strong affinity with drugs,multi-functional surface modification and high biological security.Polydopamine?PDA?with good biocompatibility has attracted wide attention due to its excellent biological adhesion and self-polymerization properties.Mesoporous/microporous nanocomposites fabricated by PDA and its unique strong metal ion chelation combined with ion groups in metal-organic frameworks?MOFs?will pave a distinctive way for the development of multifunctional drug co-loading system.In this thesis,the mesoporous-microporous drug delivery systems?DDSs?with novel structure,good performance and sequential release function was synthesized to reverse MDR of tumor cells by using the advantages of PDA and MOF.The main research contents are as follows:?1?Mesoporous-microporous PDA-MSN@ZIF-8 composite drug delivery system:sequential drug release system for reversing MDRMesoporous PDA-MSN nanoparticles with a diameter of about 100 nm were synthesized by a simple one-pot method,and then the microporous zeolitic imidazolate framework-8?ZIF-8?shell was successfully coated on the surface of PDA-MSN by a two-step coating method.PDA-MSN@ZIF-8 nanoparticles were characterised by means of Transmission electron microscopy?TEM?,Scanning electron microscopy?SEM?,Fourier transform infrared spectroscopy?FTIR?,Thermogravimetric analysis?TGA?,Dynamic light scattering?DLS?and BET.Morphology and structural analysis proved that the ZIF-8 shell with a thickness of about 10 nm was successfully synthesized on the surface of PDA-MSN.In drug loading experiment,DOX was loaded into the mesopores PDA-MSN core(607?g mg^-1)by PDA-mediated?-?stacking interaction,and the MDR inhibitor curcumin?CUR?was encapsulated in the microporous shell of ZIF-8(778?g mg^-1)during the grown process.Sustained DOX release was observed in drug release experiments followed by the earlier and faster release of CUR due to the acid-sensitive degradation of ZIF-8 shell.Furthermore,the in vitro experiments by using MCF-7/ADR and the nanocomposite nanocarrier showed good biocompatibility and effective cell uptake.More importantly,the preferential release of CUR first inhibited the drug efflux function of membrane P-glycoprotein?P-gp?,and then promoted the nuclear transport of DOX.Finally,the DDS promoted the synergistic killing effect of drug resistant cancer cells.?2?Multifunctional dual-compartment core-shell nanocomposite of MPDA@ZIF-8:efficient co-loading of hydrophilic and hydrophobic drugs,as well as biological applicationMesoporous polydopamine nanoparticles?MPDA?were prepared by the assembly of primary PDA particles and Pluronic F127 stabilized emulsion droplets on water/1,3,5-trimethylbenzene?TMB?interfaces.Subsequently,a substantial increase in zeta potential of dimethylaminoethanol?DMEA?modified MPDA from-30 mV to3.2 mV was observed.Finally,core-shell composite nanoparticles MPDA@ZIF-8 were synthesized by ZIF-8 coating.By means of Transmission electron microscopy?TEM?,Scanning electron microscopy?SEM?,Fourier transform infrared spectroscopy?FTIR?and BET,MPDA@ZIF-8 nanocomposite with a diameter of about 190 nm and a uniform shell of ZIF-8?40 nm?were obtained.Based on the adhesion property of PDA,the charge interaction between PDA and topotecan?TPT?and the rapid growth of ZIF-8on the surface of MPDA,the co-loading of TPT(120?g mg^-1)and lonidamine?LND,the MDR inhibitor?(798?g mg^-1)were successfully achieved.In drug release experiments,acid-responsive degradation of ZIF-8 resulted in faster and earlier release of LND,showing a sequential release behavior.The drug efflux function of P-gp was inhibited by LND through inhibiting glycolysis and the respiratory chain of cancer cells as well as the energy metabolism process.In addition,cytotoxicity and laser confocal experiments showed that MPDA@ZIF-8 had good biocompatibility,high efficiency of cell uptake and drug delivery,and the DDS showed good cytotoxicity toward MDR cancer cells.The results of this thesis show that in the combination therapy of reversing MDR,the newly multifunctional composite nanomaterial based on PDA and MOF has successfully realized a high payload of chemotherapeutic drug and chemosensitizer.Moreover,the effective and controllable sequential release provides drugs with favorable conditions to exert efficient function at different targets.The DDS not only enhances the inhibition of MCF-7/ADR,but also provides experimental basis for the development of mesoporous/microporous co-delivery nano-drug delivery system.