Organometallic Phyllosilicate-Gold Nanocomplex: An Effective Oral Delivery System of Methotrexate for Enhanced in vivo Efficacy Against Colorectal Cancer

Int J Nanomedicine. 2023 Dec 5:18:7257-7266. doi: 10.2147/IJN.S437860. eCollection 2023.

Abstract

Purpose: Oral administration, although convenient and preferred for treating colorectal cancer (CRC), faces challenges due to limited CRC-related intestinal positioning and a dense mucus barrier. In the present study, a gold-nanoparticle decorated-organometallic phyllosilicate nanocomposite (AC-Au), with a pH-dependent surface coating, was employed for more effective oral delivery of anticancer drugs to treat CRC.

Methods: The organometallic AC-Au was synthesized using the in-situ sol-gel method. Subsequently, methotrexate (MTX) was loaded into AC-Au, and the complex (AC-Au/MTX) was surface-coated with poly (methacrylic acid-co-methyl methacrylate) (1:2), a pH-dependent polymer (E/AC-Au /MTX). The in vitro characteristics of nanoparticles were examined using various analytical methods. In vivo efficacy studies were also conducted using an HCT-116 orthotopic colorectal cancer model.

Results: AC-Au emerged as a spherical nanoparticle with a mean size of 26.5 ± 0.43 nm, displaying a positive charge over the pH range of 2-10. Both the uncoated and coated drug-loaded nanocomplexes (AC-Au/MTX and E/AC-Au/MTX) were fabricated with high entrapment efficiency (> 80%). Various analyses, including ultraviolet-visible spectroscopy, X-ray powder diffraction, transmission electron microscopy, and energy dispersive X-ray spectroscopy, confirmed the formation of the nanocomplexes. While AC-Au/MTX achieved rapid and extensive drug release at the pH range of 1.2-7.4, E/AC-Au/MTX exhibited pH-dependent drug release, with approximately 23% at pH 1.2 and 74% at pH 7.4. Relative to free MTX, the AC-Au-based nanocomplex significantly enhanced the cytotoxicity of MTX in HCT-116 cells. Furthermore, orally administered E/AC-Au/MTX significantly improved the anti-tumor activity of MTX in an HCT-116 orthotopic colorectal cancer model, resulting in approximately 60% suppression of tumor mass compared with the positive control.

Conclusion: The organometallic AC-Au nanocomplex coated with a pH-dependent polymer has the potential to be an effective colonic drug delivery system of MTX, enhancing in vivo efficacy against colorectal cancer.

Keywords: aminoclay; colonic delivery; cytotoxicity; gold nanoparticle; methotrexate.

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Colorectal Neoplasms* / drug therapy
  • Drug Delivery Systems
  • Gold / chemistry
  • Humans
  • Methotrexate / chemistry
  • Nanoparticles*
  • Polymers
  • Silicates

Substances

  • Antineoplastic Agents
  • Gold
  • Methotrexate
  • Polymers
  • Silicates

Grants and funding

This research was supported by National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (Nos. 2019R1A2C2004873 and 2018R1A5A2023127) and the BK21 FOUR program through the National Research Foundation (NRF) funded by the Ministry of Education of Korea.