Coassembled Prodrug Nanoparticles Mitigating the Acquired Resistance to Protein Degradation Therapy

Area of Science:

• Oncology
• Nanotechnology
• Drug Delivery

Background:

• Proteolysis Targeting Chimeras (PROTACs) are promising anticancer drugs but face challenges like drug resistance.
• Acquired PROTAC resistance in tumors is linked to elevated expression of the ABCB1/MDR1 drug efflux pump.
• Overcoming this resistance is crucial for effective PROTAC cancer therapy.

Purpose of the Study:

• To develop a novel nanoplatform to combat acquired PROTAC resistance in cancer.
• To inhibit PROTAC efflux and overcome MDR1-mediated resistance.
• To enhance the therapeutic efficacy of PROTACs in resistant tumors.

Main Methods:

• Engineered a coassembled PROTAC nanoplatform using alkylated PROTAC prodrugs and human serum albumin (HSA).
• Encapsulated the mTOR inhibitor rapamycin (RAPA) within the nanoplatform to inhibit extracellular PROTAC efflux.
• Investigated the hydrolysis of PROTAC prodrugs by intracellular esterases and the inhibition of MDR1 expression by RAPA.

Main Results:

• The nanoplatform effectively restored PROTAC activity by intracellular hydrolysis.
• Rapamycin (RAPA) successfully inhibited MDR1 expression, mitigating MDR1-associated PROTAC resistance.
• The coassembled nanoplatform demonstrated high efficiency in suppressing tumor growth in a PROTAC-resistant breast cancer mouse model.

Conclusions:

• The developed PROTAC nanoplatform effectively overcomes acquired PROTAC resistance.
• This approach, validated with multiple PROTACs, shows generality for combating drug efflux pump-mediated resistance.
• The nanoplatform holds significant potential for treating PROTAC-resistant cancers.