Cell-Penetrating Peptide and α-Tocopherol-Conjugated Poly(amidoamine) Dendrimers for Improved Delivery and Anticancer Activity of Loaded Paclitaxel.

Even though existing chemotherapeutic agents, including paclitaxel (PTX), possess superior anticancer activity, their application is limited because of extreme hydrophobicity. Here, a dendrimer-based nanoparticles system has been prepared for improved delivery of loaded paclitaxel to the tumor. The cell-penetrating peptides, octa-arginine (R) and vitamin-E succinate (VES), had been conjugated to the PEGylated generation 4 polyamidoamine dendrimer (D) to form RVES-PD. The synthesized polymers had been characterized by 1 NMR, IR, and gel permeation chromatography. The PTX-loaded RVES-PD (RVES-PD-PTX) was physicochemically characterized for particle size, zeta potential analysis, drug loading, release, and encapsulation studies. Cellular uptake, cytotoxicity, and apoptosis determination studies were carried out in human lung cancer cells (A549) in monolayers and spheroids. In vivo antitumor efficacy of RVES-PD-PTX was determined using B16F10 tumor-bearing mice. The results indicated that the RVES-PD nanoparticles were taken up by cancer cells effectively and demonstrated improved cellular translocation compared to nontargeted VES-PD. The cytotoxicity study revealed that RVES-PD-PTX exhibited the highest cytotoxicity of PTX compared to nontargeted VES-PD-PTX and free PTX in the PTX concentration range of 0-50 μg/mL. RVES-PD-PTX-induced apoptosis as analyzed by the Annexin V assay and suppressed the growth of spheroids to the highest extent compared to VES-PD-PTX and free PTX. Furthermore, the biodistribution study indicated that the RVES-PD had higher accumulation in tumor compared to VES-PD. The in vivo experiment using B16F10 tumor-bearing mice demonstrated that the RVES-PD treatment resulted in the highest rate of tumor volume reduction and apoptosis primarily by upregulating caspase 3/7 to the highest extent compared to VES-PD and free PTX. In conclusion, the developed RVES-PD could load PTX and showed efficient cell penetration and improved PTX-mediated cytotoxicity in all tested in vitro and in vivo assay systems. The results strongly suggest further exploration of this developed PTX-nanoformulation in cancer treatment.