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

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.

Research Advances of Lipid Nanoparticles in the Treatment of Colorectal Cancer

“… 79 The development of non-biodegradable NPs such as polymeric NPs, LNPs, micelles, gold NPs (AuNPs), and magnetic NPs marked a significant advancement in the targeted formulation and delivery of therapeutic agents to the affected sites in the colon and rectum. 31 , 80–84 Researchers have used NPs as drug delivery vehicles in clinical trials for CRC treatment ( Table 1 ). In particular, LNPs stand out as a highly promising nanomedicine delivery system owing to their excellent biodegradability, biocompatibility, straightforward structural design, and the ability to tailor their functionality to specific needs.…”

“… 104 For example, Bajracharya et al used poly (methacrylic acid-co-methyl methacrylate) (1:2) as a surface coating to prepare E/AC-Au/MTX nanocomplexes. 31 These nanocomplexes exhibited a remarkable entrapment efficiency of over 80% while demonstrating notable pH-response characteristics. Musa et al loaded NPs in the form of soft agglomerates, which reduced premature drug release.…”

“…In fact, in intestinal disease, LNP-based DDSs have been extensively studied for their ability to target lesion sites. 30 , 31 They minimize drug exposure to normal tissues while maintaining therapeutic concentrations at the lesion site, effectively inhibiting tumor growth. 32 Additionally, the composition, size, and surface charge of these NPs are crucial factors that influence their accumulation in and clearance from the intestinal mucosa.…”