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

• Published in: Bioconjugate chemistry 2021-11, Vol.32 (11), p.2353-2365
• Main Authors: Wijewantha, Nisitha, Eikanger, Morgan M, Antony, Ryan M, Potts, Rashaun A, Rezvani, Khosrow, Sereda, Grigoriy
• Format: Article
• Language: English
• Subjects: Affinity; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor agents; Blood-brain barrier; Casein; Cell Line, Tumor; Cell migration; Colon; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Colorectal carcinoma; Drug delivery; Drug Delivery Systems; Drug resistance; Enzymes; Humans; Matrilysin; Metastases; Nanoparticles; Nanoparticles - chemistry; Porosity; Proteins; Side effects; Silica; Silicon dioxide; Silicon Dioxide - chemistry; Therapy; Tumor cells; Tumors; Veratridine
• ISSN: 1043-1802; 1520-4812; 1520-4812
• DOI: 10.1021/acs.bioconjchem.1c00416

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.