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Aptamer-armed nanostructures improve the chemotherapy outcome of triple-negative breast cancer
Quanyuan Wan1, Zihua Zeng1, Jianjun Qi1
1Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA.
Abstract:
Triple-negative breast cancer is an aggressive subtype of breast cancer that is primarily treated using systemic chemotherapy due to the lack of a specific cell surface marker for drug delivery. Cancer cell-specific aptamer-mediated drug delivery is a promising targeted chemotherapy for marker-unknown cancers. Using a poorly differentiated carcinoma cell-specific DNA aptamer (PDGC21T), we formed a self-assembling circinate DNA nanoparticle (Apt21TNP) that binds triple-negative breast cancer cells. Using our previously designed pH-sensitive dendrimer-conjugated doxorubicin (DDOX) as the payload, we found that each nanoparticle loaded 30 doxorubicin molecules to form an Apt21TNP-DDOX nanomedicine that is stable in human plasma. Upon cell binding, Apt21TNP-DDOX is internalized by triple-negative breast cancer cells through the macropinocytosis pathway. Once inside cells, the low pH microenvironment in lysosomes induces doxorubicin drug payload release from Apt21TNP-DDOX. Our in vitro studies demonstrate that Apt21TNP-DDOX can preferentially bind triple-negative breast cancer cells to induce cell death. Furthermore, we show that Apt21TNP-DDOX can accumulate in subcutaneous MDA-MB-231 tumors in mice following systemic administration to reduce tumor burden, minimize side effects, and improve animal survival. Together, our results demonstrate that Apt21TNP-mediated doxorubicin delivery is a potent, targeted chemotherapy for triple-negative breast cancer that may alleviate side effects in patients.
Insights
Targeted chemotherapy using DNA nanoparticles loaded with doxorubicin effectively kills triple-negative breast cancer cells. This novel nanomedicine shows promise for reducing tumor burden and improving survival in preclinical models.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) lacks specific cell surface markers, complicating targeted drug delivery.
- Systemic chemotherapy is the primary treatment but often causes significant side effects.
- Aptamer-mediated drug delivery offers a promising strategy for targeting cancer cells, even in marker-unknown cancers.
Purpose of the Study:
- To develop and evaluate a novel aptamer-mediated drug delivery system for TNBC.
- To investigate the efficacy of a DNA nanoparticle loaded with doxorubicin for targeted TNBC treatment.
Main Methods:
- A poorly differentiated carcinoma cell-specific DNA aptamer (PDGC21T) was used to form a self-assembling DNA nanoparticle (Apt21TNP).
- The nanoparticle was loaded with pH-sensitive dendrimer-conjugated doxorubicin (DDOX), forming Apt21TNP-DDOX.
- In vitro studies assessed cell binding, internalization via macropinocytosis, and drug release in lysosomes.
- In vivo studies evaluated tumor accumulation, tumor burden reduction, and survival in a mouse model.
Main Results:
- Apt21TNP-DDOX nanoparticles were stable in human plasma and preferentially bound and were internalized by TNBC cells.
- Internalization led to doxorubicin release in the lysosomal environment, inducing cancer cell death.
- Systemic administration in mice resulted in tumor accumulation, reduced tumor burden, and improved survival.
Conclusions:
- Aptamer-mediated doxorubicin delivery via Apt21TNP-DDOX is a potent and targeted chemotherapy for TNBC.
- This nanomedicine approach demonstrates potential for alleviating treatment side effects in TNBC patients.
