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Integrating Proteolysis-Targeting Chimeras (PROTACs) with Delivery Systems for More Efficient and Precise Targeted

Jiachan Lin1, Zirui Chen1, Dan Zhang1

  • 1School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.

Macromolecular Rapid Communications
|April 4, 2025
PubMed

Insights

Targeted protein degradation (TPD) with proteolysis-targeting chimeras (PROTACs) offers new cancer therapy options. Delivery system innovations are improving PROTAC efficacy and reducing toxicity for better clinical translation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Targeted protein degradation (TPD) utilizes proteolysis-targeting chimeras (PROTACs) to degrade oncogenic proteins, a promising cancer treatment strategy.
  • PROTACs leverage the ubiquitin-proteasome pathway (UPS) for selective protein degradation, overcoming limitations of traditional inhibitors and targeting undruggable proteins.
  • Challenges include poor solubility, low cell permeability, and potential systemic toxicity, hindering PROTACs' clinical application.

Purpose of the Study:

  • To review advancements in drug delivery systems for PROTACs to enhance in vivo degradation efficacy.
  • To discuss strategies for reducing off-target effects and improving pharmacokinetic properties of PROTACs.
  • To highlight the potential of combining PROTACs with delivery systems for improved cancer therapy.

Main Methods:

  • Review of current literature on PROTAC delivery strategies.
  • Analysis of nanoparticle-based delivery, covalent modification prodrugs, multi-headed PROTACs, and microneedle systems.
  • Discussion of design principles, challenges, and therapeutic potential of these delivery systems.

Main Results:

  • Various delivery strategies, including nanoparticles and prodrugs, show promise in enhancing PROTAC performance.
  • Innovative PROTAC designs and microneedle systems offer new avenues for targeted delivery and improved efficacy.
  • These integrated approaches aim to overcome the pharmacokinetic and toxicity limitations of PROTACs.

Conclusions:

  • Integrating PROTACs with advanced delivery systems is crucial for overcoming current limitations.
  • Delivery strategies can significantly improve in vivo degradation efficacy and reduce systemic toxicity.
  • The combination holds substantial promise for accelerating the clinical translation of PROTAC-based cancer therapies.
Keywords:
PROTACsdrug delivery systemnanoparticlesprodrugsprotein degradation

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