Related Experiment Video
Updated: Jun 27, 2025
Modeling Brain Metastasis by Internal Carotid Artery Injection of Cancer Cells
Published on: August 2, 2022
Simultaneous targeting of peripheral and brain tumors with a therapeutic nanoparticle to disrupt metabolic
Akash Ashokan1,2, Shrita Sarkar1,2, Mohammad Z Kamran1,2
1NanoTherapeutics Research Laboratory, Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136.
Abstract:
Brain metastasis of advanced breast cancer often results in deleterious consequences. Metastases to the brain lead to significant challenges in treatment options, as the blood-brain barrier (BBB) prevents conventional therapy. Thus, we hypothesized that creation of a nanoparticle (NP) that distributes to both primary tumor site and across the BBB for secondary brain tumor can be extremely beneficial. Here, we report a simple targeting strategy to attack both the primary breast and secondary brain tumors utilizing a single NP platform. The nature of these mitochondrion-targeted, BBB-penetrating NPs allow for simultaneous targeting and drug delivery to the hyperpolarized mitochondrial membrane of the extracranial primary tumor site in addition to tumors at the brain. By utilizing a combination of such dual anatomical distributing NPs loaded with therapeutics, we demonstrate a proof-of-concept idea to combat the increased metabolic plasticity of brain metastases by lowering two major energy sources, oxidative phosphorylation (OXPHOS) and glycolysis. By utilizing complementary studies and genomic analyses, we demonstrate the utility of a chemotherapeutic prodrug to decrease OXPHOS and glycolysis by pairing with a NP loaded with pyruvate dehydrogenase kinase 1 inhibitor. Decreasing glycolysis aims to combat the metabolic flexibility of both primary and secondary tumors for therapeutic outcome. We also address the in vivo safety parameters by addressing peripheral neuropathy and neurobehavior outcomes. Our results also demonstrate that this combination therapeutic approach utilizes mitochondrial genome targeting strategy to overcome DNA repair-based chemoresistance mechanisms.
Insights
This study introduces dual-targeting nanoparticles to treat breast cancer brain metastases by inhibiting key energy pathways in both primary and secondary tumors, improving therapeutic outcomes.
Area of Science:
- Oncology
- Nanotechnology
- Biochemistry
Background:
- Brain metastasis from advanced breast cancer presents significant therapeutic challenges due to the blood-brain barrier (BBB).
- Conventional treatments are often ineffective against brain metastases, necessitating novel delivery strategies.
- Metabolic plasticity, particularly increased energy demands, is a hallmark of brain metastases.
Purpose of the Study:
- To develop a nanoparticle (NP) platform capable of targeting both primary breast tumors and secondary brain metastases.
- To investigate a combination therapy that simultaneously inhibits oxidative phosphorylation (OXPHOS) and glycolysis in tumors.
- To assess the in vivo safety and efficacy of this dual-targeting nanotherapeutic approach.
Main Methods:
- Design of mitochondrion-targeted, BBB-penetrating nanoparticles for dual drug delivery.
- Utilizing a chemotherapeutic prodrug to decrease OXPHOS and a pyruvate dehydrogenase kinase 1 inhibitor to reduce glycolysis.
- Conducting complementary studies and genomic analyses to evaluate therapeutic effects.
- Assessing in vivo safety through peripheral neuropathy and neurobehavioral outcome studies.
Main Results:
- Demonstrated successful dual targeting of primary and brain metastatic breast cancer sites with a single NP platform.
- Showcased a combination therapy that effectively lowers OXPHOS and glycolysis in both tumor types.
- Provided proof-of-concept for overcoming metabolic plasticity and chemoresistance mechanisms.
- Evaluated in vivo safety, indicating potential for clinical translation.
Conclusions:
- Developed a novel nanotherapeutic strategy for simultaneously targeting primary and brain metastatic breast cancer.
- This approach effectively combats tumor metabolic plasticity by inhibiting key energy pathways.
- The dual-targeting NPs offer a promising platform for overcoming chemoresistance and improving treatment outcomes for brain metastases.
More Related Videos
09:02Author Spotlight: Innovative Cancer Therapies with Iron Oxide Nanoparticles for Glioblastoma Treatment
Published on: September 27, 2024
07:25Author Spotlight: Multimodal Imaging Strategies for Optimizing Drug Delivery and Early Detection in Glioblastoma Treatment
Published on: March 1, 2024
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...