Engineering Novel DNA Nanoarchitectures for Targeted Drug Delivery and Aptamer mediated Apoptosis in Cancer...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Targeted cancer therapy requires precise drug delivery to cancer stem cells (CSCs) to improve efficacy and reduce toxicity.
• Acute myeloid leukemia (AML) relapse is often driven by leukemic stem cells (LSCs) that evade conventional treatments.
• Current targeted therapies face challenges with specificity due to biomarker expression on healthy tissues.

Purpose of the Study:

• To develop and evaluate Designer DNA Architecture (DDA)-templated Drug Conjugates (DDA-DCs) for targeted delivery of daunorubicin (Dau) to AML LSCs.
• To investigate the potential of DDA-DCs to overcome minimal residual disease (MRD) and prevent AML relapse.
• To demonstrate the advantages of DDA-DC strategy over existing targeted therapies.

Main Methods:

• DDA-DCs were engineered with CD117- and CD123-binding aptamers for LSC targeting.
• Daunorubicin (Dau) was loaded into DDA platforms via dsDNA intercalation.
• Cytotoxicity and efficacy of DDA-DCs were assessed in vitro (ex vivo) and in vivo AML models.

Main Results:

• DDA-DCs demonstrated potent and selective cytotoxicity against CD117+CD123+ AML cells.
• Effective drug dosage was reduced by 500-fold ex vivo and up to 10-fold in vivo.
• The DDA-DC strategy showed advantages including biomarker profiling for targeting, titratable affinity, and multidrug delivery capabilities.

Conclusions:

• DDA-DCs represent a promising strategy for highly specific and potent delivery of anticancer drugs to LSCs.
• This approach offers superior anticancer efficacy with minimized off-target effects, addressing critical needs in AML treatment.
• The DDA-DC platform provides a versatile framework for developing next-generation targeted cancer therapies.