A Triphenylphosphonium-Functionalized Mitochondriotropic Nanocarrier for Efficient Co-Delivery of Doxorubicin and
Katerina N Panagiotaki1, Zili Sideratou2, Spiros A Vlahopoulos3
1Institute of Nanoscience and Nanotechnology, NCSR ''Demokritos", 15310 Aghia Paraskevi, Greece. knpanagiotaki@gmail.com.
Abstract:
Drug delivery systems that target subcellular organelles and, in particular, mitochondria are considered to have great potential in treating disorders that are associated with mitochondrial dysfunction, including cancer or neurodegenerative diseases. To this end, a novel hyperbranched mitochondriotropic nanocarrier was developed for the efficient co-delivery of two different (both in chemical and pharmacological terms) bioactive compounds. The carrier is based on hyperbranched poly(ethyleneimine) functionalized with triphenylphosphonium groups that forms ~100 nm diameter nanoparticles in aqueous media and can encapsulate doxorubicin (DOX), a well-known anti-cancer drug, and chloroquine (CQ), a known chemosensitizer with arising potential in anticancer medication. The anticancer activity of this system against two aggressive DOX-resistant human prostate adenocarcinoma cell lines and in in vivo animal studies was assessed. The co-administration of encapsulated DOX and CQ leads to improved cell proliferation inhibition at extremely low DOX concentrations (0.25 μΜ). In vivo experiments against DU145 human prostate cancer cells grafted on immunodeficient mice resulted in tumor growth arrest during the three-week administration period and no pervasive side effects. The findings put forward the potential of such targeted low dose combination treatments as a therapeutic scheme with minimal adverse effects.
Insights
This study developed a novel nanocarrier for targeted mitochondrial drug delivery. The system effectively co-delivers doxorubicin and chloroquine, inhibiting cancer cell growth with minimal side effects.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Pharmacology
Background:
- Mitochondrial dysfunction is implicated in diseases like cancer and neurodegenerative disorders.
- Targeting mitochondria with drug delivery systems offers therapeutic potential.
- Developing efficient carriers for co-delivery of multiple drugs is crucial.
Purpose of the Study:
- To develop a novel hyperbranched mitochondriotropic nanocarrier for co-delivery of doxorubicin (DOX) and chloroquine (CQ).
- To evaluate the anticancer efficacy of this system against DOX-resistant prostate cancer cells in vitro and in vivo.
Main Methods:
- Synthesis of a hyperbranched poly(ethyleneimine) nanocarrier functionalized with triphenylphosphonium groups.
- Encapsulation of doxorubicin (anti-cancer drug) and chloroquine (chemosensitizer).
- Assessment of anticancer activity in DOX-resistant human prostate adenocarcinoma cell lines and in vivo xenograft mouse models.
Main Results:
- The nanocarrier efficiently co-delivered DOX and CQ, achieving significant cell proliferation inhibition at very low DOX concentrations (0.25 μM).
- In vivo studies demonstrated complete tumor growth arrest in mice bearing DU145 prostate cancer xenografts over a three-week period.
- No significant adverse side effects were observed in the in vivo experiments.
Conclusions:
- The developed mitochondriotropic nanocarrier shows promise for targeted co-delivery of anticancer drugs.
- Low-dose combination therapy facilitated by this system offers a potential therapeutic strategy with reduced toxicity.
- This approach could be valuable for treating mitochondrial dysfunction-related diseases, including resistant cancers.
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