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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
Defined Host-Guest Chemistry on Nanocarbon for Sustained Inhibition of Cancer
Fatemeh Ostadhossein1, Santosh K Misra1, Prabuddha Mukherjee1
1Department of Bioengineering, University of Illinois at Urbana-Champaign, 1304 W. Springfield Ave., Urbana, IL, 61801, USA.
Abstract:
Signal transducer and activator of transcription factor 3 (STAT-3) is known to be overexpressed in cancer stem cells. Poor solubility and variable drug absorption are linked to low bioavailability and decreased efficacy. Many of the drugs regulating STAT-3 expression lack aqueous solubility; hence hindering efficient bioavailability. A theranostics nanoplatform based on luminescent carbon particles decorated with cucurbit[6]uril is introduced for enhancing the solubility of niclosamide, a STAT-3 inhibitor. The host-guest chemistry between cucurbit[6]uril and niclosamide makes the delivery of the hydrophobic drug feasible while carbon nanoparticles enhance cellular internalization. Extensive physicochemical characterizations confirm successful synthesis. Subsequently, the host-guest chemistry of niclosamide and cucurbit[6]uril is studied experimentally and computationally. In vitro assessments in human breast cancer cells indicate approximately twofold enhancement in IC50 of drug. Fourier transform infrared and fluorescence imaging demonstrate efficient cellular internalization. Furthermore, the catalytic biodegradation of the nanoplatforms occur upon exposure to human myeloperoxidase in short time. In vivo studies on athymic mice with MCF-7 xenograft indicate the size of tumor in the treatment group is half of the controls after 40 d. Immunohistochemistry corroborates the downregulation of STAT-3 phosphorylation. Overall, the host-guest chemistry on nanocarbon acts as a novel arsenal for STAT-3 inhibition.
Insights
This study introduces a novel nanoplatform using carbon particles and cucurbit[6]uril to improve the solubility and delivery of niclosamide, a STAT-3 inhibitor, enhancing cancer treatment efficacy.
Area of Science:
- Nanotechnology
- Materials Science
- Biomedical Engineering
Background:
- Signal transducer and activator of transcription factor 3 (STAT-3) is overexpressed in cancer stem cells.
- Hydrophobic drugs like niclosamide face bioavailability challenges due to poor solubility, limiting their efficacy.
- Developing effective drug delivery systems is crucial for targeting STAT-3 in cancer therapy.
Purpose of the Study:
- To develop a theranostic nanoplatform for enhancing the solubility and cellular uptake of niclosamide, a STAT-3 inhibitor.
- To investigate the host-guest chemistry between cucurbit[6]uril and niclosamide for improved drug delivery.
- To evaluate the in vitro and in vivo efficacy of the nanoplatform in inhibiting STAT-3 and reducing tumor growth.
Main Methods:
- Synthesis of luminescent carbon particles decorated with cucurbit[6]uril.
- Physicochemical characterization of the nanoplatform.
- Experimental and computational study of host-guest chemistry.
- In vitro studies using human breast cancer cells (IC50 determination, cellular internalization via FTIR and fluorescence imaging).
- In vivo studies using MCF-7 xenograft in athymic mice.
- Immunohistochemistry to assess STAT-3 phosphorylation.
Main Results:
- Successful synthesis and characterization of the nanoplatform.
- Demonstrated host-guest complexation between niclosamide and cucurbit[6]uril, enhancing drug solubility.
- Significant cellular internalization of the nanoplatform observed.
- In vitro studies showed a twofold enhancement in drug IC50.
- In vivo studies resulted in a 50% reduction in tumor size in the treatment group compared to controls.
- STAT-3 phosphorylation was downregulated, confirmed by immunohistochemistry.
Conclusions:
- The developed nanoplatform effectively enhances niclosamide solubility and cellular delivery via host-guest chemistry on nanocarbon.
- The nanoplatform demonstrates significant in vitro and in vivo efficacy in inhibiting STAT-3 and reducing tumor growth.
- This approach offers a novel strategy for STAT-3 targeted cancer therapy, overcoming drug bioavailability limitations.
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