EpCAM-targeted betulinic acid analogue nanotherapy improves therapeutic efficacy and induces anti-tumorigenic immune response in colorectal cancer tumor microenvironment.

Autor: Dutta D; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. debasmita_dutta@dfci.harvard.edu.; Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND, USA. debasmita_dutta@dfci.harvard.edu.; Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India. debasmita_dutta@dfci.harvard.edu.; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA. debasmita_dutta@dfci.harvard.edu.; Harvard Medical School, Boston, MA, USA. debasmita_dutta@dfci.harvard.edu., Al Hoque A; Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND, USA.; Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India., Paul B; Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India., Park JH; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Chowdhury C; CSIR- Indian Institute of Chemical Biology, Kolkata, India., Quadir M; Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND, USA., Banerjee S; Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.; Department of Psychology and Neuroscience Program, Central Michigan University, Mount Pleasant, MI, 48859, USA.; Department of Human Physiology, Vidyasagar University, Midnapore, 721102, West Bengal, India., Choudhury A; CSIR- Indian Institute of Chemical Biology, Kolkata, India., Laha S; CSIR- Indian Institute of Chemical Biology, Kolkata, India., Sepay N; Department of Chemistry, Jadavpur University, Kolkata, India., Boro P; CSIR- Indian Institute of Chemical Biology, Kolkata, India., Kaipparettu BA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. kaippare@bcm.edu., Mukherjee B; Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India. biswajit.mukherjee@jadavpuruniversity.in.
Jazyk: angličtina
Zdroj: Journal of biomedical science [J Biomed Sci] 2024 Aug 20; Vol. 31 (1), pp. 81. Date of Electronic Publication: 2024 Aug 20.
DOI: 10.1186/s12929-024-01069-8
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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