Highly efficient and long-acting split-and-mix proteolysis targeting chimera based on self-assembled polylactic acid.

Area of Science:

• Biotechnology
• Drug Delivery
• Molecular Biology

Background:

• Proteolysis targeting chimera (PROTAC) technology offers an "event-driven" mechanism but faces challenges with high molecular weight, polarity, and poor druggability.
• Existing chimera molecules require optimization for improved bioavailability and circulation time.

Purpose of the Study:

• To enhance the in vivo effectiveness of "chimera molecules" by combining nanotechnology and chimera technology.
• To develop a novel "Split-and-Mix" proteolysis degradation (SM-PROTAC) strategy using Polylactic acid (PLA) as a self-assembled matrix.

Main Methods:

• Incorporation of Polylactic acid (PLA), an FDA-approved biomedical material, as the self-assembled matrix for SM-PROTAC.
• Evaluation of PLA-based SM-PROTACs in cellular assays for the degradation of model targets (BRD4, ERα, CDK4).
• Assessment of in vivo tumor inhibition in female mice using PLA-based SM-PROTACs.

Main Results:

• PLA-based SM-PROTACs demonstrated successful degradation of model targets in cellular assays.
• Significant tumor inhibition was observed in vivo with PLA-based SM-PROTACs.
• These PROTACs required lower target ligand content (~1/10 of controls) and showed long-term therapeutic potential (1 injection per three days).

Conclusions:

• PLA-based SM-PROTACs exhibit promising drug characteristics, overcoming limitations of previous peptide- and liposome-based approaches.
• The strategy offers advantages in low-dose and long-term applications, enhancing the pharmaceutical potential of SM-PROTAC technology.
• This study provides valuable insights into the application of nanotechnology-enhanced PROTACs for improved therapeutic outcomes.