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Published on: September 13, 2022
Targeted therapy of colon cancer with aptamer-functionalized albumin nanoparticles loaded with disulfiram
Yacong An1, Zhen Yu2, Ting Li3
1Biobank of Peking University First Hospital, Beijing 100034, People's Republic of China.
Abstract:
Chemotherapy remains the primary treatment for most patients with metastatic colorectal cancer (mCRC), yet its efficacy is often limited by severe adverse effects. Drug repurposing offers a promising strategy to accelerate oncology drug development. Disulfiram (DSF), a licensed anti-alcoholism agent, has demonstrated broad-spectrum anticancer activity in preclinical models. However, its clinical translation for oncology is hindered by poor aqueous solubility, rapid metabolism, and lack of tumor selectivity. To overcome these limitations, we developed a novel targeted drug delivery system (Apt-NPs-DSF) by encapsulating disulfiram (DSF) within albumin nanoparticles (NPs) functionalized with the nucleolin-targeting AS1411 aptamer. Apt-NPs-DSF had an average size of 96.4 ± 7.4 nm and was negatively charged with a zeta potential of -19.1 ± 2.2 mV. Furthermore, DSF was released from the albumin NPs with a typical sustained release profile. Apt-NPs-DSF demonstrated favorable serum stability and hemocompatibility. Of note, aptamer-guided NPs were preferentially internalized by nucleolin-expressing CT26 colon cancer cells vs control cells. Moreover,in vitrocytotoxicity assay revealed that Apt-NPs-DSF significantly enhanced the killing of CT26 colon cancer cells. Importantly,in vivostudy confirmed that Apt-NPs-DSF achieved superior antitumor efficacy without raising systemic toxicity, outperforming non-targeted counterparts. Collectively, these results suggest that Apt-NPs-DSF has potential in the targeted treatment of colon cancer.
Insights
Repurposed disulfiram (DSF) in targeted nanoparticles showed enhanced colon cancer cell killing. This novel drug delivery system demonstrated superior antitumor efficacy with reduced systemic toxicity in preclinical models.
Area of Science:
- Oncology
- Nanotechnology
- Drug Delivery
Background:
- Metastatic colorectal cancer (mCRC) treatment relies on chemotherapy, often limited by toxicity.
- Drug repurposing, like using disulfiram (DSF), offers a promising avenue for cancer therapy.
- DSF's clinical use is restricted by poor solubility, rapid metabolism, and lack of tumor selectivity.
Purpose of the Study:
- To develop a targeted drug delivery system for disulfiram (DSF) to overcome its limitations in cancer treatment.
- To enhance the efficacy and tumor selectivity of DSF for metastatic colorectal cancer (mCRC).
Main Methods:
- Encapsulation of DSF within albumin nanoparticles (NPs) functionalized with the AS1411 aptamer for nucleolin targeting (Apt-NPs-DSF).
- Characterization of Apt-NPs-DSF size, charge, drug release, serum stability, and hemocompatibility.
- Evaluation of cellular uptake in nucleolin-expressing cancer cells and assessment of in vitro cytotoxicity and in vivo antitumor efficacy.
Main Results:
- Apt-NPs-DSF exhibited optimal nanoparticle characteristics (96.4 ± 7.4 nm, -19.1 ± 2.2 mV) with sustained DSF release.
- Preferential internalization of Apt-NPs-DSF by nucleolin-expressing colon cancer cells was observed.
- Enhanced in vitro cytotoxicity against CT26 colon cancer cells and superior in vivo antitumor efficacy with minimal systemic toxicity were achieved.
Conclusions:
- The novel Apt-NPs-DSF system effectively overcomes DSF's limitations for targeted colon cancer therapy.
- This targeted nanoparticle formulation shows significant potential for improving mCRC treatment outcomes.
- Apt-NPs-DSF represents a promising strategy for developing safer and more effective cancer drugs.
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