The Synthesis and Anticancer Activity of the Trastuzumab-Doxorubicin Antibody-Drug Conjugate Using Strain-Promoted...

Area of Science:

• Bioconjugation Chemistry
• Cancer Therapeutics
• Molecular Oncology

Background:

• Antibody-drug conjugates (ADCs) are targeted cancer therapies with several approved treatments.
• Existing antibody-drug conjugates (ADCs) and their individual components (trastuzumab, doxorubicin) have associated safety concerns.
• Strain-promoted alkyne-azide cycloaddition (SPAAC) offers a "green" conjugation strategy.

Purpose of the Study:

• To create a novel antibody-drug conjugate (ADC) by linking trastuzumab and doxorubicin.
• To utilize the strain-promoted alkyne-azide coupling (SPAAC) reaction for ADC synthesis.
• To evaluate the efficacy of the novel ADC in a human breast tumor cell line.

Main Methods:

• Conjugation of trastuzumab with doxorubicin via strain-promoted alkyne-azide coupling (SPAAC).
• Characterization of the resulting antibody-drug conjugate (ADC).
• Assessment of ADC-induced changes in proapoptotic markers (Bax, cleaved caspase 9, Cytc) in BT474 cells.

Main Results:

• Successful synthesis of a trastuzumab-doxorubicin ADC using the "green" SPAAC reaction.
• The novel ADC demonstrated increased levels of proapoptotic markers Bax, cleaved caspase 9, and Cytc.
• These effects were observed at concentrations of 5 and 10 μg/mL in the BT474 human breast tumor cell line.

Conclusions:

• The SPAAC reaction provides an efficient and regioselective method for ADC synthesis.
• The developed trastuzumab-doxorubicin ADC shows promise as a targeted cancer therapy.
• This approach may help mitigate safety issues associated with individual drug components.