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Published on: February 6, 2015
Nanotechnology-based strategies for overcoming clinical limitations of PROTACs in cancer therapy
Hanhee Cho1,2, Jinseong Kim1, Hoyeon Lee1,3
1Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea. kimkm@ewha.ac.kr.
Abstract:
Proteolysis-targeting chimeras (PROTACs) have emerged as a promising next-generation therapeutic modality by enabling complete degradation of target proteins rather than transient inhibition. However, increasing clinical studies have reported adverse effects of PROTACs that resemble those observed with conventional small-molecule drugs, highlighting the need for strategies to improve tumor specificity and reduce systemic toxicity. To overcome these limitations, tumor-targeted approaches have attracted considerable attention, particularly through the development of triggered-activatable PROTACs and advanced delivery systems. In this review, we introduce recent advances in stimuli-activatable PROTACs, including those responsive to pH, enzymatic activity, and external stimuli, as well as nanotechnology-based delivery platforms such as lipid-, polymer-, albumin-, and peptide-based systems. These developments with hybrid systems are expected to facilitate the clinical translation of PROTACs by providing spatially controlled and tumor-specific therapeutic interventions.
Insights
Proteolysis-targeting chimeras (PROTACs) offer targeted protein degradation. Strategies like stimuli-activatable PROTACs and nanodelivery systems enhance tumor specificity and reduce toxicity, improving clinical translation.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Proteolysis-targeting chimeras (PROTACs) represent a novel therapeutic strategy for targeted protein degradation.
- Clinical studies reveal PROTACs can cause adverse effects similar to conventional drugs, necessitating improved tumor specificity and reduced systemic toxicity.
Purpose of the Study:
- To review recent advancements in tumor-targeted PROTACs.
- To explore strategies for enhancing PROTACs' clinical applicability through improved specificity and reduced toxicity.
Main Methods:
- Review of stimuli-activatable PROTACs (pH, enzymatic, external stimuli).
- Analysis of nanotechnology-based delivery platforms (lipid, polymer, albumin, peptide).
- Examination of hybrid systems combining activation and delivery.
Main Results:
- Stimuli-activatable PROTACs offer controlled activation in tumor microenvironments.
- Nanotechnology platforms facilitate targeted delivery and enhanced therapeutic efficacy.
- Hybrid systems integrate these approaches for spatially controlled interventions.
Conclusions:
- Tumor-targeted approaches, including stimuli-activatable PROTACs and advanced nanodelivery systems, are crucial for overcoming PROTAC limitations.
- These strategies are expected to significantly facilitate the clinical translation of PROTACs for cancer therapy.
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