Targeting Colon Cancer Cells with Enzyme-Triggered Casein-Gated Release of Cargo from Mesoporous Silica-Based Nanoparticles

Abstract

Colorectal cancer (CRC) is one of the most widely diagnosed cancers worldwide. Despite notable improvements in therapeutic strategies available to CRC patients, late stages of CRC have a higher incidence rate of drug resistance, which is associated with a higher mortality rate. The development of therapeutic strategies that use nanoparticles as a drug delivery system has become one of the most promising potential approaches for cancer therapy. Previous studies have shown that a natural plant alkaloid, veratridine (VTD), suppresses colon cancer cell migration and invasion, two essential factors in tumor metastasis, through activation of the gene that encodes the tumor-suppressor protein UBXN2A. The goal of this study is to develop a nanoassembly to selectively deliver VTD to cancer cells and release it on demand while leaving normal cells intact. We packaged the targeted therapy anticancer molecule VTD inside mesoporous silica nanoparticles (MSNs) impermeable to the blood-brain barrier (BBB) and with selective affinity to CRC cells and sealed the VTD-loaded nanoparticles with an enzymatically cleavable protein. The particles will deliver and release VTD only at the targeted colorectal tumor sites. Since the enzyme MMP-7 protease is dominantly secreted by CRC cells, the release triggered by the enzymes will increase VTD concentration at tumor cells, enhancing the efficiency of the new therapy. We have proven the selective affinity of two types of VTD-carrying particles to CRC cells and enzyme-or acid-triggered VTD release. Negatively surface-charged MSNs showed significant affinity toward positively charged cancer cells but not negatively charged normal fibroblast colon cells, making VTD-MSNs a promising anticancer drug with minimal side effects.

DNA Delivery to Intact Plant Cells by Casein Nanoparticles with Confirmed Gene Expression

“…Additionally, plant MMPs are phylogenetically close to human MMP‐7. [ 67 ] The enzymatic activity of NtMMP1 obeyed Michaelis‐Menten kinetics. The computed k cat / Km value, determined to be 5.74 × 10 4 ± 0.5 × 10 4 M −1 s −1 , is similar to the k cat / Km value of the human MMP‐7 for the same substrate.…”

Targeting the Gut: A Systematic Review of Specific Drug Nanocarriers

“…pH responsiveness appears to be a recurrent method to deliver drugs to the gut, given the peculiar pH variations that are intrinsic to the gastrointestinal tract in pathophysiological conditions. pH responsiveness is expressed by several polymers, such as alginate/sodium alginate, HA, and eudragits and also by silica particles [ 76 , 77 , 78 , 109 , 139 , 140 , 339 ]. In particular, HA seems to be a highly versatile molecule for gut targeting, being not only pH sensitive but also the natural ligand for CD44 receptor, which is overexpressed in several gut pathological conditions, such as colorectal cancer.…”

Colorectal cancer therapy mediated by nanomedicines

“…Without any casein, 86.13% of the loaded veratridine leaked from VTD-MSN-COOH within 48 h, which was significantly higher than that (19.4%) with casein modification, demonstrating the good performance of avoiding drug premature release of casein. 39 Moreover, Mehwish Abid and co-workers reported oligoester-crosslinked dextran-based enzyme-responsive nanoparticles, which released encapsulated 5-FU specifically in response to the dextranase enzyme in the colonic environment. 41 Xia and co-workers constructed core–shell nanoparticles by covalently combining Gly-Phe-Leu-Gly (GFLG) with the hydrophobic block of a block copolymer.…”