Dual Peptide-Modified Nanoparticles Improve Combination Chemotherapy of Etoposide and siPIK3CA Against Drug-Resistant...

Small cell lung carcinoma (SCLC) is a highly aggressive form of malignancy with rapid recurrence and poor prognosis. The dual peptide-modified nanoparticles (NPs) for improving chemotherapy against drug-resistant small cell lung carcinoma cells has been developed. In this study, the SCLC targeting ligand, antagonist G peptide (AG), and cell-penetrating peptide, TAT, modified NPs were used to encapsulate both anticancer drugs etoposide (ETP) and PIK3CA small-interfering RNA (siPIK3CA). The ETP@NPs and siRNA@NPs had particle size 201.0 ± 1.9-206.5 ± 0.7 nm and 155.3 ± 12.4-169.1 ± 11.2 nm, respectively. The lyophilized ETP@NPs and siRNA@NPs maintained their particle size and zeta potential during 28-day storage without severe aggregation or dissociation. Either ETP@NPs or siRNA@NPs significantly reduced the IC₅₀ of drugs by 2.5-5.5 folds and 2.4-3.9 folds, respectively, as compared to free ETP and siRNA/PEI nanocomplex in drug-resistant CD133(+) H69 cells. Herein, the IC₅₀ of dual-peptide modified ETP@NPs and siRNA@NPs were prominently lower than single-peptide modified NPs. The synergistic effect (CI < 1) was further observed in co-treatment of ETP and siPIK3CA particularly delivered by dual-peptide modified NPs.