Language
English
Publication Date
8-20-2024
Journal
Journal of Biomedical Science
DOI
10.1186/s12929-024-01069-8
PMID
39164686
PMCID
PMC11334571
PubMedCentral® Posted Date
8-20-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Background: Betulinic acid (BA) has been well investigated for its antiproliferative and mitochondrial pathway-mediated apoptosis-inducing effects on various cancers. However, its poor solubility and off-target activity have limited its utility in clinical trials. Additionally, the immune modulatory role of betulinic acid analogue in the tumor microenvironment (TME) is largely unknown. Here, we designed a potential nanotherapy for colorectal cancer (CRC) with a lead betulinic acid analogue, named as 2c, carrying a 1,2,3-triazole-moiety attached to BA through a linker, found more effective than BA for inhibiting CRC cell lines, and was chosen here for this investigation. Epithelial cell adhesion molecule (EpCAM) is highly overexpressed on the CRC cell membrane. A single-stranded short oligonucleotide sequence, aptamer (Apt), that folds into a 3D-defined architecture can be used as a targeting ligand for its specific binding to a target protein. EpCAM targeting aptamer was designed for site-specific homing of aptamer-conjugated-2c-loaded nanoparticles (Apt-2cNP) at the CRC tumor site to enhance therapeutic potential and reduce off-target toxicity in normal cells. We investigated the in vitro and in vivo therapeutic efficacy and anti-tumorigenic immune response of aptamer conjugated nanotherapy in CRC-TME.
Methods: After the characterization of nanoengineered aptamer conjugated betulinic acid nanotherapy, we evaluated therapeutic efficacy, tumor targeting efficiency, and anti-tumorigenic immune response using cell-based assays and mouse and rat models.
Results: We found that Apt-2cNP improved drug bioavailability, enhanced its biological half-life, improved antiproliferative activity, and minimized off-target cytotoxicity. Importantly, in an in vivo TME, Apt-2cNP showed promising signs of anti-tumorigenic immune response (increased mDC/pDC ratio, enhanced M1 macrophage population, and CD8 T-cells). Furthermore, in vivo upregulation of pro-apoptotic while downregulation of anti-apoptotic genes and significant healing efficacy on cancer tissue histopathology suggest that Apt-2cNP had predominantly greater therapeutic potential than the non-aptamer-conjugated nanoparticles and free drug. Moreover, we observed greater tumor accumulation of the radiolabeled Apt-2cNP by live imaging in the CRC rat model.
Conclusions: Enhanced therapeutic efficacy and robust anti-tumorigenic immune response of Apt-2cNP in the CRC-TME are promising indicators of its potential as a prospective therapeutic agent for managing CRC. However, further studies are warranted.
Keywords
Colorectal Neoplasms, Animals, Tumor Microenvironment, Betulinic Acid, Mice, Pentacyclic Triterpenes, Epithelial Cell Adhesion Molecule, Humans, Nanoparticles, Cell Line, Tumor, Rats, Betulinic acid analogue, EpCAM, Aptamer, Colorectal cancer, Tumor-microenvironment, Immune response
Published Open-Access
yes
Recommended Citation
Dutta, Debasmita; Al Hoque, Ashique; Paul, Brahamacharry; et al., "EpCAM-Targeted Betulinic Acid Analogue Nanotherapy Improves Therapeutic Efficacy and Induces Anti-tumorigenic Immune Response in Colorectal Cancer Tumor Microenvironment" (2024). Faculty, Staff and Students Publications. 6396.
https://digitalcommons.library.tmc.edu/baylor_docs/6396
Graphical Abstract