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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
An AS1411 aptamer-conjugated liposomal system containing a bubble-generating agent for tumor-specific chemotherapy
Zi-Xian Liao1, Er-Yuan Chuang2, Chia-Chen Lin2
1Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC.
Abstract:
Recent research in chemotherapy has prioritized overcoming the multidrug resistance (MDR) of cancer cells. In this work, liposomes that contain doxorubicin (DOX) and ammonium bicarbonate (ABC, a bubble-generating agent) are prepared and functionalized with an antinucleolin aptamer (AS1411 liposomes) to target DOX-resistant breast cancer cells (MCF-7/ADR), which overexpress nucleolin receptors. Free DOX and liposomes without functionalization with AS1411 (plain liposomes) were used as controls. The results of molecular dynamic simulations suggest that AS1411 functionalization may promote the affinity and specific binding of liposomes to the nucleolin receptors, enhancing their subsequent uptake by tumor cells, whereas plain liposomes enter cells with difficulty. Upon mild heating, the decomposition of ABC that is encapsulated in the liposomes enables the immediate activation of generation of CO2 bubbles, creating permeable defects in their lipid bilayers, and ultimately facilitating the swift intracellular release of DOX. In vivo studies in nude mice that bear tumors demonstrate that the active targeting of AS1411 liposomes can substantially increase the accumulation of DOX in the tumor tissues relative to free DOX or passively targeted plain liposomes, inhibiting tumor growth and reducing systemic side effects, including cardiotoxicity. The above findings indicate that liposomes that are functionalized with AS1411 represent an attractive therapeutic alternative for overcoming the MDR effect, and support a potentially effective strategy for cancer therapy.
Insights
This study developed novel AS1411-functionalized liposomes loaded with doxorubicin (DOX) and a bubble-generating agent. These liposomes effectively target multidrug-resistant (MDR) breast cancer cells, enhancing drug delivery and reducing side effects.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Multidrug resistance (MDR) in cancer cells is a major challenge in chemotherapy.
- Doxorubicin (DOX) is a common chemotherapy drug with limited efficacy against MDR cells.
- Nucleolin receptors are overexpressed on DOX-resistant breast cancer cells (MCF-7/ADR).
Purpose of the Study:
- To develop and evaluate AS1411-functionalized liposomes for targeted delivery of DOX to MDR breast cancer cells.
- To investigate the mechanism of drug release triggered by bubble generation within liposomes.
- To assess the in vivo efficacy and safety of these targeted liposomes in a preclinical cancer model.
Main Methods:
- Preparation and characterization of AS1411-functionalized liposomes containing DOX and ammonium bicarbonate (ABC).
- Molecular dynamic simulations to predict AS1411 binding affinity to nucleolin receptors.
- In vitro assessment of cellular uptake and drug release.
- In vivo studies in nude mice bearing tumors to evaluate therapeutic efficacy and systemic toxicity.
Main Results:
- AS1411 functionalization enhanced liposome affinity and specific binding to nucleolin receptors, improving tumor cell uptake.
- Encapsulated ABC generated CO2 bubbles upon mild heating, creating defects for rapid intracellular DOX release.
- In vivo studies showed increased DOX accumulation in tumors, significant tumor growth inhibition, and reduced cardiotoxicity compared to free DOX or plain liposomes.
- AS1411 liposomes demonstrated superior therapeutic efficacy in overcoming MDR.
Conclusions:
- AS1411-functionalized liposomes represent a promising strategy for overcoming doxorubicin resistance in breast cancer.
- The bubble-generating system facilitates efficient intracellular drug release, enhancing therapeutic outcomes.
- This targeted liposomal delivery system offers a potential advancement in cancer therapy with reduced systemic side effects.
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