In a recent article published in Signal Transduction and Targeted Therapy, researchers introduced polymer-based nano-PROteolysis Targeting Chimeras (PROTACs) to address ongoing challenges in targeted cancer therapies.
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These nano-PROTACs are specifically designed to enhance the delivery and efficacy of treatments for colorectal cancer (CRC), a malignancy known for its resistance to conventional therapies, including immune checkpoint inhibitors. By leveraging advanced nanotechnology, the researchers aim to improve therapeutic outcomes for CRC patients.
Background
Colorectal cancer remains a significant health concern globally, characterized by its complex biology and resistance to various treatment modalities. Traditional therapies often fail to achieve satisfactory results due to the tumor’s ability to evade therapeutic agents.
PROTACs represent a promising alternative, as they can induce targeted protein degradation, thereby eliminating the function of oncogenic proteins. However, their effectiveness is often compromised by poor pharmacokinetics and biodistribution.
The study addresses these limitations by introducing polymer PROTACs conjugated with pH-sensitive and enzyme-sensitive nanoparticles (PSRNs). These nanoparticles are engineered to respond to the tumor microenvironment, facilitating enhanced accumulation and internalization within cancer cells.
The Current Study
The study systematically developed and evaluated polymer-based nano-PROTACs (PSRNs) for enhanced delivery and efficacy in colorectal cancer therapy.
The synthesis of PSRNs involved the conjugation of PROTACs with polymers that exhibit ultra-pH sensitivity and responsiveness to cathepsin B, an enzyme prevalent in the tumor microenvironment. Specifically, PEG-b-P(EPA-r-PROTAC) was dissolved in dimethyl sulfoxide (DMSO) and added to deionized water under sonication.
Following the removal of DMSO via ultrafiltration, the PSRNs were obtained as a yellow suspension. For the preparation of polymer nano-PROTACs (PNRNs), PEG-b-P(EH-r-PROTAC) was utilized, following the same protocol.
In vivo experiments were conducted using male BALB/c mice (18–20 g) purchased from Peking University Health Science Center. A CT26 tumor model was established by subcutaneously injecting 1 × 105 CT26 cells into the right flank of the mice. All animal procedures adhered to the ethical guidelines set forth by the Animal Ethics Committee of Peking University (protocol LA2020345).
Pharmacokinetic studies assessed the circulation time of PSRNs and PNRNs. The elimination half-lives were determined, and tissue distribution was evaluated through in vivo imaging techniques. Mice were administered PSRNs or PNRNs, and fluorescence imaging tracked the accumulation of nanoparticles in tumor tissues over time.
To assess the penetration capability of PSRNs, 3D multicellular tumor spheroids were employed as an in vitro model. Spheroids derived from human breast cancer (MCF-7), mouse colorectal cancer (CT26), and pancreatic cancer (PANC-1) were incubated with Cy5-labeled PSRNs at varying pH levels (7.4 and 6.6) for 8 hours. Confocal laser scanning microscopy (CLSM) was used to visualize the penetration efficacy of the nanoparticles within the spheroids.
Results and Discussion
The results indicated that the polymer-based nano-PROTACs (PSRNs) effectively maintained their structural integrity during circulation, enabling significant accumulation in tumor tissues. This accumulation was primarily attributed to the enhanced permeation and retention (EPR) effect, which is a critical factor in tumor targeting.
In vitro experiments revealed that PSRNs exhibited a pH-dependent degradation of target proteins, indicating their responsiveness to the acidic environment characteristic of tumors. This feature is particularly advantageous, as it allows for selective action within the tumor microenvironment, enhancing the therapeutic potential of PROTACs.
In vivo studies using CT26-bearing mice showed that treatment with PSRNs, especially in combination with immune checkpoint inhibitors, resulted in markedly improved survival rates compared to control groups receiving standard therapies. The synergistic effect observed suggests that combining PSRNs with immune modulation could significantly enhance the overall efficacy of treatment regimens for colorectal cancer.
Pharmacokinetic analysis confirmed the favorable biodistribution of PSRNs, with real-time fluorescence imaging illustrating their effective targeting of tumor sites. This dynamic tracking provided valuable insights into the behavior of the nanoparticles within the biological system, reinforcing their potential as a viable delivery system for PROTACs.
Conclusion
The development of polymer-based nano-PROTACs represents a significant advancement in targeted cancer therapy. By addressing the challenges of tissue penetration and cellular internalization, PSRNs offer a promising approach to enhance the delivery and efficacy of PROTACs in colorectal cancer treatment.
The study’s findings provide a strong foundation for further research into the clinical application of these innovative nanoparticles, with the potential to improve outcomes for patients suffering from this challenging malignancy.
Future investigations will be essential to optimize the formulation and explore the broader applicability of PSRNs in other cancer types, ultimately contributing to the evolution of precision medicine in oncology.
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Journal Reference
Yang L., et al. (2024). Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy. Signal Transduction and Target Therapy. DOI: 10.1038/s41392-024-01983-1, https://www.nature.com/articles/s41392-024-01983-1
