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Nucleolin-aptamer therapy in retinoblastoma: molecular changes and mass spectrometry-based imaging
Nithya Subramanian1,2, Amitava Srimany3, Jagat R Kanwar2
1Department of Nanobiotechnology, Vision Research Foundation, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Chennai, India.
Abstract:
Retinoblastoma (RB) is an intraocular childhood tumor which, if left untreated, leads to blindness and mortality. Nucleolin (NCL) protein which is differentially expressed on the tumor cell surface, binds ligands and regulates carcinogenesis and angiogenesis. We found that NCL is over expressed in RB tumor tissues and cell lines compared to normal retina. We studied the effect of nucleolin-aptamer (NCL-APT) to reduce proliferation in RB tumor cells. Aptamer treatment on the RB cell lines (Y79 and WERI-Rb1) led to significant inhibition of cell proliferation. Locked nucleic acid (LNA) modified NCL-APT administered subcutaneously (s.c.) near tumor or intraperitoneally (i.p.) in Y79 xenografted nude mice resulted in 26 and 65% of tumor growth inhibition, respectively. Downregulation of inhibitor of apoptosis proteins, tumor miRNA-18a, altered serum cytokines, and serum miRNA-18a levels were observed upon NCL-APT treatment. Desorption electrospray ionization mass spectrometry (DESI MS)-based imaging of cell lines and tumor tissues revealed changes in phosphatidylcholines levels upon treatment. Thus, our study provides proof of concept illustrating NCL-APT-based targeted therapeutic strategy and use of DESI MS-based lipid imaging in monitoring therapeutic responses in RB.
Insights
Nucleolin aptamer therapy effectively inhibits retinoblastoma (RB) cell proliferation and tumor growth in mice. This targeted approach shows promise for treating this childhood eye cancer by altering key molecular markers.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Retinoblastoma (RB) is a severe intraocular childhood cancer leading to blindness and mortality if untreated.
- Nucleolin (NCL) is a protein overexpressed on RB tumor cells, implicated in cancer progression and angiogenesis.
- Targeting NCL presents a potential therapeutic strategy for RB.
Purpose of the Study:
- To investigate the therapeutic potential of a nucleolin-aptamer (NCL-APT) against retinoblastoma.
- To evaluate the efficacy of NCL-APT in inhibiting RB cell proliferation and tumor growth.
- To explore the molecular mechanisms and imaging techniques associated with NCL-APT treatment.
Main Methods:
- Treatment of RB cell lines (Y79, WERI-Rb1) with NCL-APT.
- In vivo studies using Y79 xenografted nude mice treated with NCL-APT (subcutaneous and intraperitoneal).
- Analysis of apoptosis proteins, miRNA levels, serum cytokines, and lipid profiles using DESI MS imaging.
Main Results:
- NCL-APT significantly inhibited proliferation in RB cell lines.
- NCL-APT treatment resulted in 26% (s.c.) and 65% (i.p.) tumor growth inhibition in mice.
- Treatment led to downregulation of apoptosis inhibitors, tumor miRNA-18a, altered serum cytokines, and changes in phosphatidylcholines.
Conclusions:
- NCL-APT demonstrates significant therapeutic potential for retinoblastoma.
- This study validates NCL-APT as a targeted therapy strategy for RB.
- DESI MS imaging is a valuable tool for monitoring therapeutic responses in RB treatment.
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