PROTAC Delivery Strategies for Overcoming Physicochemical Properties and Physiological Barriers in Targeted Protein Degradation
Proteolysis targeting chimeras (PROTACs), heterobifunctional molecules that hijack the ubiquitin–proteasome system (UPS) to degrade specific proteins, hold great promise in treating diseases driven by traditionally “undruggable” targets. However, their large molecular weight, high hydrophobicity, an...
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| Format: | Article |
| Language: | English |
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MDPI AG
2025-04-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/17/4/501 |
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| author | Endry Wahyu Syahputra Hyunji Lee Hyukjun Cho Hyun Jin Park Kwang-Su Park Duhyeong Hwang |
| author_facet | Endry Wahyu Syahputra Hyunji Lee Hyukjun Cho Hyun Jin Park Kwang-Su Park Duhyeong Hwang |
| author_sort | Endry Wahyu Syahputra |
| collection | DOAJ |
| description | Proteolysis targeting chimeras (PROTACs), heterobifunctional molecules that hijack the ubiquitin–proteasome system (UPS) to degrade specific proteins, hold great promise in treating diseases driven by traditionally “undruggable” targets. However, their large molecular weight, high hydrophobicity, and other physicochemical hurdles contribute to their limited bioavailability, suboptimal pharmacokinetics, and attenuated therapeutic efficacy. Consequently, diverse formulation innovations have been investigated to optimize PROTAC delivery. This review examines current challenges and advances in specialized drug delivery approaches designed to bolster PROTAC pharmacological performance. We first outline the fundamental limitations of PROTACs—their low aqueous solubility, poor cell permeability, rapid clearance, and concentration-dependent “hook effect”. We then discuss how various enabling formulations address these issues, including polymeric micelles, emulsions, amorphous solid dispersions, lipid-based nanoparticles, liposomes, and exosomes. Collectively, these delivery technologies substantially improve the therapeutic outcomes of PROTACs in preclinical cancer models. Future applications may extend beyond oncology to address other complex diseases using newly emerging heterobifunctional molecules. By integrating advanced formulation science with innovative degrader design, the field stands poised to unlock the clinical potential of PROTACs for protein degradation therapies. |
| format | Article |
| id | doaj-art-79a46dda71c949a2bf5d172283dc403d |
| institution | DOAJ |
| issn | 1999-4923 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj-art-79a46dda71c949a2bf5d172283dc403d2025-08-20T03:13:45ZengMDPI AGPharmaceutics1999-49232025-04-0117450110.3390/pharmaceutics17040501PROTAC Delivery Strategies for Overcoming Physicochemical Properties and Physiological Barriers in Targeted Protein DegradationEndry Wahyu Syahputra0Hyunji Lee1Hyukjun Cho2Hyun Jin Park3Kwang-Su Park4Duhyeong Hwang5College of Pharmacy, Keimyung University, Daegu 42601, Republic of KoreaCollege of Pharmacy, Kyungsung University, Busan 48434, Republic of KoreaCollege of Pharmacy, Keimyung University, Daegu 42601, Republic of KoreaCollege of Pharmacy, Keimyung University, Daegu 42601, Republic of KoreaCollege of Pharmacy, Keimyung University, Daegu 42601, Republic of KoreaCollege of Pharmacy, Keimyung University, Daegu 42601, Republic of KoreaProteolysis targeting chimeras (PROTACs), heterobifunctional molecules that hijack the ubiquitin–proteasome system (UPS) to degrade specific proteins, hold great promise in treating diseases driven by traditionally “undruggable” targets. However, their large molecular weight, high hydrophobicity, and other physicochemical hurdles contribute to their limited bioavailability, suboptimal pharmacokinetics, and attenuated therapeutic efficacy. Consequently, diverse formulation innovations have been investigated to optimize PROTAC delivery. This review examines current challenges and advances in specialized drug delivery approaches designed to bolster PROTAC pharmacological performance. We first outline the fundamental limitations of PROTACs—their low aqueous solubility, poor cell permeability, rapid clearance, and concentration-dependent “hook effect”. We then discuss how various enabling formulations address these issues, including polymeric micelles, emulsions, amorphous solid dispersions, lipid-based nanoparticles, liposomes, and exosomes. Collectively, these delivery technologies substantially improve the therapeutic outcomes of PROTACs in preclinical cancer models. Future applications may extend beyond oncology to address other complex diseases using newly emerging heterobifunctional molecules. By integrating advanced formulation science with innovative degrader design, the field stands poised to unlock the clinical potential of PROTACs for protein degradation therapies.https://www.mdpi.com/1999-4923/17/4/501PROTACdrug delivery systemphysicochemical propertysolubilizationbioavailability |
| spellingShingle | Endry Wahyu Syahputra Hyunji Lee Hyukjun Cho Hyun Jin Park Kwang-Su Park Duhyeong Hwang PROTAC Delivery Strategies for Overcoming Physicochemical Properties and Physiological Barriers in Targeted Protein Degradation Pharmaceutics PROTAC drug delivery system physicochemical property solubilization bioavailability |
| title | PROTAC Delivery Strategies for Overcoming Physicochemical Properties and Physiological Barriers in Targeted Protein Degradation |
| title_full | PROTAC Delivery Strategies for Overcoming Physicochemical Properties and Physiological Barriers in Targeted Protein Degradation |
| title_fullStr | PROTAC Delivery Strategies for Overcoming Physicochemical Properties and Physiological Barriers in Targeted Protein Degradation |
| title_full_unstemmed | PROTAC Delivery Strategies for Overcoming Physicochemical Properties and Physiological Barriers in Targeted Protein Degradation |
| title_short | PROTAC Delivery Strategies for Overcoming Physicochemical Properties and Physiological Barriers in Targeted Protein Degradation |
| title_sort | protac delivery strategies for overcoming physicochemical properties and physiological barriers in targeted protein degradation |
| topic | PROTAC drug delivery system physicochemical property solubilization bioavailability |
| url | https://www.mdpi.com/1999-4923/17/4/501 |
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