Intracellular Paclitaxel Delivery Facilitated by a Dual-Functional CPP with a Hydrophobic Hairpin Tail.


Wei Y(1)(2), Zhang M(3), Jiao P(1), Zhang X(1), Yang G(4)(5), Xu X(4)(5)(2).
Author information:
(1)School of Life Science and Technology, Nanyang Normal University, Nanyang, Henan Province 473061, P.R. China.
(2)State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, P.R. China.
(3)Department of Oncology, Nanyang First People's Hospital, Henan Province, 473002, P.R. China.
(4)Biochemical Engineering Research Centre, Anhui University of Technology, Ma'anshan, Anhui Province 243032, P.R. China.
(5)School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui Province 243032, P.R. China.


In our pervious study, a dual-functional peptide R7 was developed to form a complex with paclitaxel (PTX) for enhancement of PTX translocation. However, because of the unstable noncovalent bond between R7 and PTX, PTX redistributed after the introduction of heparin, leading to R7-PTX complex dissociation, further causing less PTX penetration than expected. Thus, a novel positive CPP carrier of P9 was developed to improve CPP-PTX affinity via a double-proline (Pro, P) hairpin tail and enhance PTX translocation through the reduction of translocation energy barrier, confirmed by the MM-PBSA analysis and umbrella sampling simulation. Cellular uptake study reveals that P9 can quickly translocate into the HeLa cells within 1 min and exhibits no noticeable cytotoxicity. Compared to R7, P9 is able to help PTX translocation, leading to a remarkable increase in the intracellular concentration of PTX, eventually resulting in a significant loss in tumor cell viability. In vivo experiments demonstrate that a vein injection of P9-PTX complex dramatically inhibits tumor growth. Our study provides a novel perspective for designing CPP-facilitated drug carrier to enhance antitumor efficiency.