Lung cancer immunochemotherapy: Codelivery of EGFR tki and PTX via an immunostimulatory dual functional nanocarrier.

Abstract

e15177 Background: Immuno-target therapy combines a target therapy agent with an immune modulating agent and represents an attractive approach to improve cancer therapy.However, the success of it is hampered by the lack of a strategy to effectively co deliver the two therapeutics to the tumours.Here we report an improved dual functional nanocarrier (PEG5k-Fmoc-NLG2) to load Gefitinib for improved cancer Immuno target therapy.PEG5K-Fmoc-NLG2 is a prodrug that can inhibited IDO enzyme activity in vitro,while IDO1 inhibition reversed T cell suppression mediated by IDO expressing mouse cancer cells. Methods: Gefitinib loaded in carrier was prepared via a film hydrationmethod,the physicochemical properties of micelles was determined by TEM and particle size test.The cytotoxicity of the drug was detected by MTT assay. 3LL lung cancer was inoculated in mice and different drugs was injected through the tail vein to compare the anti tumor effect of drug loading micells with existing targeted drug gefitinib and CTLA4 antibody; tumor tissue proteins were extracted to clarify changes in pEGFR expressionexpression; flow cytometry will be finished to observe tumor immune microenvironment changes. Results: 1. Gefitinib loaded micelle maintain the similar size with blank PEG5k-fmoc-NLG2 micelles that is around 20nm.The drug-loaded micelles produced uniformed size and morphology. which further confirmed the size of micelles was around 20nm. 2. PTX and Gefitinib loaded in PEG5k-fmoc-NLG2 exhibited significantly enhanced tumor cell killing effect than the free drug on both A549 and 3LL cell lines. 3. The antitumor efficacy of different drugs loaded in the carrier were tested in a murine lung cancer model (3LL). All treatment showed significant better antitumor activity compared to the control group, Gefitinib/PEG5k-Fmoc-NLG2 plus CTLA4 antibody exhibited the best antitumor effect. Antitumor activity of gefitinib loaded in carrier was comparable with free gefitinib alone. 4. With various treatments the expression of p-EGFR protein level varied. Basically, compare with free gefitinib alone, the carrier loaded gefitinib was more effective in the inhibition of EGFR phosphorylation. Conclusions: We have shown that targeted delivery of PTX and Gefitinib via a immunostimulatory nanocarrier effectively improved drugs antitumor activity. More study about tumor immune microenvironment are required. Such strategy can be employed in novel therapy combining chemotherapy drugs and immunemodulating agents such as PD-1 and CTLA4.