| Lung cancer,known as primary bronchial carcinoma,is the most common type of malignancy in clinical diagnosis and the most deadly cancer worldwide,posing a serious threat to human life and health.Currently,the clinical treatment for lung cancer is based on chemotherapeutic drugs,surgical resection,radiation therapy and biological immunotherapy.With the continuous progress of clinical medicine,these traditional treatment strategies have been improved and developed.However,the cure rate and prognosis status of patients have not been significantly elevated by these therapies.Therefore,exploring new treatment strategies has become a top priority in the prevention and treatment for lung cancer.Traditional Chinese medicine(TCM)is an important branch of traditional medical culture in China and has been used for thousands of years.In the long-term practice of disease treatment,TCM has been demonstrated to possess unique anti-tumor properties and has been widely accepted as a mainstream complementary and alternative therapy.In addition,with the increasing understanding on the mechanisms of cancer development at the genetic level and the maturity of molecular biology manipulation techniques,gene therapy based on oligonucleotides is gradually developing as an emerging therapeutic tool and is potential to be widely used in the clinical treatment of cancer.However,the intake of small molecule drugs or gene-based“drugs”used to treat cancer is mainly by oral or injectable routes.Both of these delivery methods result in a systematic random distribution of the drugs,which not only greatly reduces its bioavailability,but also causes toxic effects on normal tissues and organs.In fact,the special physiological characteristics of the abundant pulmonary capillaries,the large total alveolar surface area as well as the small distance between the epithelial cells and the blood vessels for the transport of substances determine the rapid and adequate absorption of drugs through the lungs.Therefore,the construction of stable and safe drug delivery carriers to achieve in situ drug delivery in the lung may become a more direct and effective way in the treatment of lung cancer.Among various carrier materials,poly(lactic-co-glycolic acid)(PLGA)is an FDA-approved biomedical polymer with high biocompatibility and biodegradability.The porous microspheres prepared by PLGA have the characteristics of low density,weak interaction and adjustable particle size,which endow the porous microspheres with superior aerodynamic properties and make them more suitable for the delivery to lungs,and thus it is an ideal inhalable drug delivery system.Based on the above background,we prepared a safe and efficient delivery system of porous PLGA microspheres for carrying TCM monomer with gene“drug”,and achieved the goal of treating lung cancer by in situ delivery of drugs through inhalation.The detailed contents and results are summarized as follows:(1)Delivery of artesunate by inhalable porous PLGA microspheres for the treatment of lung cancerArtesunate is a semi-synthetic derivative of artemisinin,a traditional Chinese antimalarial drug,which can induce the apoptosis of a variety of cancer cells effectively.In this study,we constructed porous PLGA microspheres by double emulsion solvent volatilization method,using PLGA and artesunate as the carrier and drug,respectively.Firstly,the porous microspheres were characterized by scanning electron microscopy(SEM),nuclear magnetic resonance hydrogen spectroscopy(~1H NMR)and Fourier infrared spectroscopy(FT-IR),which confirmed that the porous microspheres exhibited a hollow,surface porous structure with a suitable aerodynamic particle size,and that the encapsulation of artesunate was successfully achieved.In vitro release profile showed that the porous microspheres had good degradation ability and could slowly release artesunate for more than 8 days.Then the anti-tumor effect and related mechanism of the release solution from porous microsphere were systematically investigated using human lung cancer cell line A549 as a model.The results showed that the release solution from microspheres could activate the caspase cascade signaling pathway and induce the apoptosis as well as the cellular G2 phase arrest,thereby facilitating the inhibition of proliferation of tumor cells.In addition,the wound healing and Transwell migration assays demonstrated that the release solution could effectively inhibit the migration and invasion of A549 cells.The above research has laid a good foundation for the subsequent construction of drug and gene co-delivery inhalable microsphere system,and also provide an important basis for studying the effects and mechanisms of drug action at the cytological level.(2)Co-delivery of icariin and miR-23b by inhalable porous PLGA microspheres for the treatment of lung cancerIcariin is a flavonoid compound extracted from the traditional Chinese medicinal plant Epimedium spp,which can exert significant anti-tumor effects by inducing apoptosis,blocking cell cycle,enhancing body immunity,regulating cell signaling and inhibiting tumor metastasis.miR-23b is a pleiotropic molecule that can regulate multiple pathways in tumor cells by targeting different genes and involve multiple life events of tumor cells such as proliferation,differentiation,apoptosis,cell adhesion,migration and infiltration.In the study,we constructed an inhalable co-delivery system of icariin and miR-23b using PLGA porous microspheres as a carrier.Using A549 cells and metastatic lung cancer mice as models,we systematically investigated the therapeutic effects and mechanisms of this delivery system in the treatment of lung cancer.This research showed that porous PLGA microspheres achieved high encapsulation of drug and gene with suitable aerodynamic particle size and excellent sustained drug release properties.The in vitro studies showed that icariin and miR-23b release solution of co-loaded microspheres could be effectively internalized by A549cells,which could in turn induce the cell apoptosis as well as G1 phase arrest of cells,thereby achieving synergistic inhibition of proliferation,metastasis and invasion of lung cancer cells.The results of in vivo studies showed that after the inhalation administration in mice,porous PLGA microspheres could achieve effective deposition in the lungs and release icariin and miR-23b.These two released components could act on the lung tumor lesions continuously,and demonstrated significant therapeutic effect by inducing the apoptosis and inhibiting the tumor growth.In addition,the PLGA microspheres and their loading components did not cause side effects to the body,making the delivery system to be used as a safe and effective treatment model.In summary,we constructed a kind of highly efficient and safe inhalation delivery system using PLGA as a carrier,which achieved the encapsulation of artesunate,or the codelivery of icariin and miR-23b.The delivery system exhibited good anti-tumor efficacy on lung cancer,and proposed a new idea for the construction of codelivery system of small molecule drugs and genes based on porous PLGA microspheres.Meanwhile,it provided a novel platform for the inhalation method to achieve in situ treatment of lung cancer. |
PDF Full Text Request