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Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Multitalented Hybrid Targeted Nanoconstructs Selectively Repress Survival Genes and Induce Breast Tumor Regression In
Niladri Haldar1,2, Rajkumar Samanta1,2, Surajit Patra1,2
1Nanobioscience, Agharkar Research Institute, Pune, India.
Abstract:
Dysregulation of survival genes is a significant factor in the development of breast cancer and other cancers. Transcriptional downregulation of these genes offers a promising therapeutic strategy for cancer treatment by inducing apoptosis. Reducing expressions of these genes by RNA interference-mediated silencing is a potential strategy for more effective gene suppression. The research developed a novel protamine biopolymer-modified GSH-responsive biodegradable mesoporous silica nanoparticle system to suppress MCL-1 and Survivin genes' transcriptional activity in MCF-7 tumor-bearing mice. The nanocarriers were characterized using techniques like DLS, XRD, FTIR, GSH-utilization, SEM, and TEM. The nanocarriers were tested for their ability to deliver siRNAs into target cells, and their toxic behavior was assessed in vitro and in vivo. The nanocarriers' gene silencing and anti-cancer efficacy were assessed in both in vitro and in vivo models. The study revealed that synthesized MUC1 aptamer-conjugated protamine-modified nanocarriers (MPPM) offer stability to siRNAs, target MCF-7 tumor, and induce apoptosis with dual siRNAs. Additionally, the MPPM nanocarrier demonstrated significant potential for targeting the MCF-7 tumor in the mice model, and the histological findings suggested its biosafety profile. The siMCL-1/siSur@MPPM nanocarriers demonstrated a significant anti-tumor effect in an in vivo mice model through the silencing of target genes and the induction of apoptosis. These results indicate that the biodegradable siMCL-1/siSur@MPPM nanocarrier provides a significant combination of targeted delivery, biodegradability, effective gene silencing, and reduced off-target effects, suggesting its potential as a promising nanomedicine for breast cancer treatment.
Insights
This study introduces a novel nanoparticle system for breast cancer therapy. The system effectively silences key survival genes (MCL-1 and Survivin) in tumor cells, leading to apoptosis and significant anti-tumor effects in mice.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Dysregulation of survival genes (e.g., MCL-1, Survivin) is crucial in breast cancer development.
- Transcriptional downregulation of these genes via RNA interference offers a therapeutic strategy by inducing apoptosis.
- Effective gene suppression requires advanced delivery systems for enhanced efficacy and reduced side effects.
Purpose of the Study:
- To develop and evaluate a novel protamine biopolymer-modified, GSH-responsive, biodegradable mesoporous silica nanoparticle system.
- To investigate the system's ability to suppress MCL-1 and Survivin gene expression in MCF-7 breast cancer cells.
- To assess the in vitro and in vivo anti-cancer efficacy and biosafety of the developed nanocarrier system.
Main Methods:
- Synthesis and characterization of protamine-modified, MUC1 aptamer-conjugated, GSH-responsive silica nanoparticles (MPPM).
- Loading of siRNAs targeting MCL-1 and Survivin genes into the nanocarriers (siMCL-1/siSur@MPPM).
- In vitro and in vivo evaluation of siRNA delivery, gene silencing, apoptosis induction, anti-tumor efficacy, and biosafety in MCF-7 tumor-bearing mice.
Main Results:
- The MPPM nanocarriers demonstrated stability, targeted delivery to MCF-7 tumors, and effective siRNA loading.
- siMCL-1/siSur@MPPM induced significant gene silencing of MCL-1 and Survivin, leading to apoptosis in cancer cells.
- In vivo studies showed a significant anti-tumor effect, with histological findings indicating a favorable biosafety profile.
Conclusions:
- The biodegradable siMCL-1/siSur@MPPM nanocarrier system offers targeted delivery, efficient gene silencing, and biodegradability for breast cancer treatment.
- This nanomedicine demonstrates potential for effective cancer therapy by inducing apoptosis and reducing off-target effects.
- The developed system shows promise as a novel therapeutic approach for managing breast cancer.
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