Alectinib Loaded Magetic Targeting Nanparticles For EML4-ALK Positive Lung Adenocarcinoma Therapy

ObjectiveAt present,the prevalence and mortality of lung cancer rank first in all malignant tumors worldwide.Non-small cell lung cancer(NSCLC)are approximately present in 85%of patients with lung cancer.Echinoderm microtubule-associated protein-like 4-gene and the anaplastic lymphoma kinase gene(EML4-ALK)is among the most common molecular targets of NSCLC.Alectinib is a clinically available anaplastic lymphoma Kinase(ALK)inhibitor,showing remarkable activity against ALK-rearranged NSCLC.However,several studies have demonstrated that the use of alectinib increased the incidence and the risk of toxicity,highlighting the need of novel therapeutic strategies to further improve the clinical application of alectinib.In the last years,the development of nanoparticles has become an innovative breakthrough in biology and medicine area.In addition,the magnetic-field-driven smart nanoparticle has the unique properties that can be used efficiently in the aspects of targeted therapy and drug delivery,reducing the toxicity of the drugs and improving the therapeutic effect.Therefore,we designed and explored a magnetic field driven alectinib nanoparticle(denoted as DATPPEA&F)for improved delivery efficiency to the tumor cell and intracellular precisely controlled release.MethodsHerein,we prepared a polymer nanocarrier which is modified by TAT peptide to load alectinib(denoted as TPPEA).At the cellular level,we found that TPPEA significantly improved the ability to kill tumor cells.In vivo experiments,helping to solve the problem that how the alectinib to be delivered into the deep tumor cell effectively,we use the tumor acidity activatable polymer composite(DATAT-PEG-b-PHEP),Fe3O4 magnetic nanoparticles(OA@Fe3O4),and alectinib to prepare the magnetic-field-driven nanoparticle(DATPPEA&F)by self-assembly under ultrasound.The surface TAT is masked by 2,3-dimethylmaleic anhydride(DA),thus the penetrating function of TAT peptide can temporarily shield.Meanwhile,DATPPEA&F which attracted by an external magnetic field was easier to accumulate in the tumor site.After that,the DA of DATPPEA&F will be off by the tumor microenvironment whose extracellular pH(pHe)is significantly acid,so as to restore the TAT peptide function and promote the cell uptake by tumor cell.ResultsThe enhanced delivery efficiency to tumor cell and the ability to inhibit tumor growth efficiently of DATPPEA&F is validated by both in vivo experiments.What’s more,the side effect of the drug can be minimized by DATPPEA&F resulting from the fact of blood biochemical indicators.Conclusionsuch cascade dual-targeted polymeric nanocarrier exhibited superior therapeutic effects and induced tumor shrinking in vivo.Meanwhile,this dual-targeted nanocarrier also minimized the alectinib-induced hepatotoxicity,providing an efficient strategy to extend the application of alectinib for NSCLC patients.