Construction of Curcumin and Paclitaxel Co-Loaded Lipid Nano Platform and Evaluation of Its Anti-Hepatoma Activity in vitro and Pharmacokinetics in vivo

Abstract

Purpose

The present study aimed to construct a co-loading platform encapsulating curcumin and paclitaxel at ratios of 2:1–80:1 (w/w) designated “CU-PTX-LNP” and explored the synergistic effects of CU-PTX at different composite proportions on liver cancer cells using the combination index (CI) method.

Methods

The CU lipid nanoplatform (CU-LNP) formulation was optimized via single-factor and orthogonal experiments. Various concentrations of PTX were added to the optimal formulation of CU-LNP to generate CU-PTX-LNP and the nanoplatform characterized via differential scanning calorimetry (DSC), transmission electron microscope (TEM), X-ray diffraction (XRD), zeta potential, polydispersity index (PDI), and size analyses. The cumulative release, stability, and cytotoxicity of CU-PTX-LNP in LO2, HepG2, and SMMC-7221 cells were assessed in vitro, followed by safety investigation and pharmacokinetic studies in vivo. The anti-tumor activity of CU-PTX-LNP was also evaluated using nude mice.

Results

CU-PTX-LNP formulations containing CU:PTX at a range of proportions (2:1–80:1; w/w) appeared as uniformly dispersed nanosized spherical particles with high entrapment efficiency (EE> 90%), sustained release and long-lasting stability. Data from in vitro cytotoxicity assays showed a decrease in the IC₅₀ value of PTX of CU-PTX-LNP (by 5.47–332.7 times in HepG2 and 4.29–143.21 times in SMMC-7221 cells) compared to free PTX. In vivo, CU-PTX-LNP displayed excellent biosafety, significant anti-tumor benefits and enhanced pharmacokinetic behavior with longer mean residence time (MRT_(0-t); CU: 4.31-fold, PTX: 4.61-fold) and half-life (t_1/2z; CU: 1.83-fold, PTX: 2.28-fold) relative to free drugs.

Conclusion

The newly designed CU-PTX-LNP platform may serve as a viable technological support system for the successful production of CU-PTX composite preparations.

Keywords:

• curcumin
• paclitaxel
• lipid nano platform
• synergistic effect

Abbreviations

CU, curcumin; PTX, paclitaxel; CU-LNP, curcumin lipid nanoplatform; CU-PTX-LNP, curcumin-paclitaxel lipid nanoplatform; DSC, differential scanning calorimetry; TEM, transmission electron microscope; XRD, X-ray diffraction; PDI, polydispersity index; MDR, multiple drug resistance; HSPC, hydrogenated soy phosphatidylcholine; PVP_K15, polyvinylpyrrolidone; HPLC, high-performance liquid chromatography; EE, encapsulation efficiency.

Acknowledgments

This study was supported by the central government guides the local science and technology development special fund (No.2022ZYD0084), the Major R&D Plan Joint Innovation Project (2022YFS0635, 2022YFS0630), the Youth Science and Technology Innovation Research Team (No. 2021JDTD0008) and the Basic Research fund (No. 2020YJ0336) of the Science and Technology Department of Sichuan province of China, the Science and Technology Innovation Team from Jiucheng Science and Technology Talent Cultivation Plan in Luzhou (No.2019-1), Key Research and Development Projectors of Luzhou (No. 2021-SYF-26), the cooperation Project (No. 210027-01SZ, 200017-01SZ) of Central Nervous System Drug Key Laboratory of Sichuan Province, Chongqing Traditional Chinese Medicine Inheritance and Innovation Team Construction Project Traditional Chinese Medicine New Drug and Safety Research Inheritance and Innovation Team” (No.2022-8).

Disclosure

The authors report no conflicts of interest in this work.