The Theranostic Research Of PLGA Hollow Microspheres Based On Gas-triggered Drug Release By Ultrasound

Cancer is a serious threat to human life and health.However,traditional chemotherapeutic drugs exists lots of disadvantages,such as fast eliminate rate,low targeting property,serious toxic and side effect and so on.Also,the diagnosis and therapy are two diverse medical treatment which make human difficult to tolerate.Thus a theranostics drug delivery system that can achieve tumor-targted,swift drug release and dense drug accumulation,effective tumor treatment and tumor diagnosis is our research topic.we have fabricated PLGA hollow microspheres that co-loaded gas-generating agent NaHCO3 and anticancer drug DOX innercore--a PLGA-DOX@NaHCO3 HMs theranostics drug delivery system.The research contents divide into three parts as follows:One part---the fabrication of PLGA-DOX@NaHCO3 HMs delivery systemWe adopted double emulsion,solvent-diffusion-evaporation method to prepare the PLGA hollow particles containing DOX and NaHCO3 innercore.The TEM micrograph depicted a hollow structure of the particles with a thickness of approximately 420 nm.The optical microscope showed the HMs were spherical in shape and dispersed uniformly.Their size was ranged from 1 to 2 ?m with a zeta potential of approximately-21.8mVUV-vis.showed the loading efficiency and amount is(39.18±2.20)%and(3.92±0.22)%.The formulations encapsulated NaHCO3-PLGA-DOX@NaHCO3 HMs could enhance the US imaging in vivo and vitro,equipping with the property of pH-responsing drug release and show higher drug accumulative release compared to the unencapsulated one-PLGA-DOX HMs.Also,when exposed to US treatment,the DOX accumulate release could be remarkably increased.Second-part:Investigation on the cytotoxic activity and tumor-targeting character of PLGA-DOX@NaHCO3 HMsIn this study,breast cancer MCF-7 cells were chosen as model cell.The result of MTT assay suggested that the cell inhibition of all formulations were time-dependent and concentration-dependent.The cell viability of PLGA-DOX@NaHCO3 HMsdeclined more remarkably compared to the PLGA-DOX HMs.Especially when given to US treatment,the cell inhibition were increased further.The cellular uptake showed the live cancer cell were more intended to uptake the pH-sensitive particles of PLGA-DOX@NaHCO3 HMs.The DOX release and accumulation is more remarkable for the PLGA-DOX@NaHCO3 HMs compared to the PLGA-DOX HMs.Flow cytometry further more examined PLGA HPs containing NaHCO3 can help DOX accumulation and rentention in MCF-7.Cell apoptosis displayed the apoptosis rate of PLGA-DOX@NaHCO3 HMs increased more markedly compared to the PLGA-DOX HMs.When exposed to US treatment,the apoptosis rate was more remarkable with the double function of chemotherapy and US energy therapy,which showing their excellent tumor-targeting property and antitumor activity.Three part:Investigating on the pharmacokinetics of PLGA-DOX@NaHCO3 HMs in vivoIn this study,we chose Kunming female mouse as model animals,adopted intratumoral injection to give PLGA-DOX@NaHCO3 HMs and intravenous injection to give free DOX,used HPLC to determine the concentration of DOX in plasma to explore the different pharmacokinetics behavior of PLGA-DOX@NaHCO3 HMs and free DOX in vivo.The result showed there existed remarkable difference of pharmacokinetics behavior between PLGA-DOX@NaHCO3 HMs and free DOX.PLGA-DOX@NaHCO3 HMs can help more drug accumulation in tumor region,reduced more drug leakage into blood vessel and other tissue,decreased the damage to normal tissue.PLGA-DOX@NaHCO3 HMs showed the prolonged half-life elimination and MRT suggesting that they can improve the bioavailability and prolong the residence time of DOX in vivo.Four part:Investigating on the pharmacodynamics and of PLGA-DOX@NaHCO3HMs in vivo.In this study,we chose S180 tumor-bearing Kunming mice as model animal,injected PLGA-DOX@NaHCO3 HMs with intratumoral vehicle and free DOX with intravenous vehicle,selected mice weight,relative tumor volume,tumor weight,tumor shape as evaluation index to explore the influence of PLGA-DOX@NaHCO3 HMs on the mice life quality and tumor inhibition.The resultshowed that PLGA-DOX@NaHCO3 HMs displayed more excellent antitumor activity compared to the PLGA-DOX HMs.When given to local US treatment,the antitumor efficacy were more markedly through the UTMD-trigged cavitation,which is comparable to the free DOX group(P>0.05).Combining with the pathology slice suggested free DOX showed the significant antitumor,but it existed serious cardiotoxicity and nephrotoxicity.PLGA-DOX@NaHCO3 HMs had barely side effect meanwhile showing remarkable antitumor efficiency with synergistic effect of US and chemotherapy,which improved the life quality of tumor-bearing mice,decreased the toxic and side effect,increased the security.We have successfully fabricated PLGA-DOX@NaHCO3 HMs delivery system.It has pH-sensitive property that can response to the acidic tumor environment and generate gas,serving for US imaging to locate tumor region.Simultaneously,gas-triggered cavitation could inhibit tumor growth.When exposed to US treatment,the ultrasound cavitation and sound-hole effect caused by ultrasound-target Microbubbles Destruction(UTMD)could increase the drug accumulation and enhance the tumor therapeutic effect.