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J. Control. Release, 2023 Feb;354:268-278 | https://doi.org/10.1016/j.jconrel.2022.12.061 Nanocracker capable of simultaneously reversing both P-glycoprotein and tumor microenvironment

Taebum Lee ^a,b,1, Kyoung Sub Kim ^b,1, Kun Na ^a,b

^aDepartment of BioMedical-Chemical Engineering, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 14662, Republic of Korea
^bDepartment of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 14662, Republic of Korea

¹These authors contributed equally to this work.
Corresponding author: Kun Na

Abstract

Here, we describe a multidrug-resistant nanocracker (MDRC) that can treat multi-drug resistant (MDR) cancer by recognizing the acidic microenvironment and inhibiting two mechanisms of MDR such as P-glycoprotein (P-gp) and vacuolar-type ATPase (V-ATPase). MDRC is a liposome formulation co-loading pantoprazole (PZ) and paclitaxel (PTX). PZ acts as a chemosensitizer that enhances the MDR cancer treatment effect of PTX by disrupting the pH gradient and inhibiting P-gp. MDRC-encapsulated PZ and PTX have different release rates, with PZ released within 12 h and PTX sustained release for 48 h in the plasma. MDRC could increase cell uptake by inhibiting the P-gp overexpressed MCF-7/mdr cells and UV-2237M cells, which are human breast MDR cancer cells and murine fibrosarcoma cells, respectively. MDRC can also increase the cytotoxic efficacy of PTX by increasing intracellular pH. MDRC has a 10.5-fold reduced IC₅₀ value in the P-gp overexpressed human breast adenocarcinoma and a 6.3- to 9.5-fold reduced IC₅₀ value in the P-gp non-expressed human breast adenocarcinoma compared to the mixture of PZ and PTX, respectively. Intravenous injection of MDRC did not cause weight loss, liver dysfunction, or major organ toxicity. MDRC exhibited 80% complete remission of murine fibrosarcoma. The excellent therapeutic effect of MDRC on MDR tumors was accompanied by an increase in dendritic cell maturation and cytotoxic T cells. In other words, MDRC has the potential to terminate MDR therapy through the complete remission of MDR tumors.

논문정보

형식Research article
게재일2023년 02월 (BRIC 등록일 2023-02-27)
연구진국내 연구진
분야 바이오·의료융합 > 바이오센싱 및 나노바이오물질

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