Design Of Natural Borneol Nanosystem For Cancer Therapy

As a non-communicable chronic disease,cancer has been one of the three killers threatening human life and health,which has become an urgent public health problem.And lung cancer has been listed as the focus of cancer prevention and treatment by the Ministry of Health,the morbidity and mortality of which have been increasing rapidly in the past 50 years.Targeted therapy and immunotherapy are considered to be effective strategies for lung cancer therapy.Gefitinib(GFT)is an effective drug targeting epidermal growth factor(EGFR)in non-small cell lung cancer(NSCLC).However,GFT will produce drug resistance,which weakens the therapeutic effect of GFT and causes toxicity to the body,thus affecting the clinical use of GFT.Natural killer(NK)cells for cancer immunotherapy exerts high potential for the treatment of NSCLC.Nevertheless,NK cells therapy is affected by tumor microenvironment,which influences the interaction between NK cells and tumor cells,leading to the reduction of tumor treatment effect.Therefore,developing sensitizers for GFT and NK cells immunotherapy are considered to be important strategies for enhancing therapeutic effect of lung cancer.In recent years,natural borneol(NB)has been studied to enhance the efficacy of antitumor drugs against cancer.However,the further application of NB has been limited due to its disadvantages,such as easy sublimation and poor water solubility.Nanotechnology has been making rapid progress in the field of biomedicine,which provides a new strategy to improve and expande the medicinal value of drugs.And oil-in-water(O/W)nanoemulsion can effectively improve solubility,uptake efficiency and bioavailability of hydrophobic drugs.Here,we synthesized O/W nanoparticles(NBNPs)to enhance the stability and water solubility of NB by using high-pressure homogenization.And then we applied it as a sensitizer to combine with GFT and NK cells in the treatment of NSCLC.The research contents were as follows:1.Oil-in-water NBNPs nanosystem was synthesized and used as a sensitizer to enhance the treatment effect of GFT against NSCLC.NBNPs displayed excellent cancer-targeted ability between A549 NSCLC cells and WI38 normal lung fibroblast cells,and outperformed NB by drastically enhancing the uptake efficiency and cytotoxicity of GFT against NSCLC growth in both cell and tumor xenograft model.Proteomic results showed that NBNPs could specifically identify einght target proteins in A549 lung cancer cells,thus enhancing the specific selectivity of NBNPs between A549 cells and WI38 cells.In addition,the sensitizing effect of NBNPs on GFT was attributed to specific binding and inhibition of EHD1 expression,which activated FADD apoptosis signal,thus causing significant apoptosis of A549 cells.The results of biosafety evaluation indicated that NBNPs in combination with GFT showed no obvious side effects on the body.More importantly,NBNPs could reduce the toxic effect of GFT on liver.2.Simultaneously,the sensitization of NBNPs to NK cells against NSCLC was studied here.It was found that NBNPs could sensitize the antitumor activity of NK cells from different patients and enhance the penetration ability of NK cells in A549 tumor spheroids.Mechanism studies showed that the combination of NBNPs and NK cells could upregulate the m RNA expression of ULBP1 and ULBP3 in A549 cells,which was beneficial to promote immunoreaction and improve the binding of NKG2 D ligands and NKG2 D,thus enhancing the NK cells antitumor effect.