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Published on: February 17, 2023
Self-assembled dual-target ibuprofen-irinotecan conjugate for colorectal cancer therapy
Lumei Dai1, Shifang Wen2, Yaling Chen2
1Affiliated Zhumadian Central Hospital of Huanghuai University, Zhumadian 463000, China; School of Biological and Food Engineering, Huanghuai University, Zhumadian 463000, China.
Abstract:
Self-assembled nanodrug conjugates utilize both hydrophilic and hydrophobic ligands for targeted tumor delivery, reducing systemic toxicity while enhancing therapeutic efficacy. Herein, four novel nonsteroidal anti-inflammatory drug (NSAID)-irinotecan (Ir) conjugates were synthesized by forming ester bonds between hydrophobic NSAIDs and hydrophilic Ir. These amphiphilic conjugates self-assembled into carrier-free NSAID-Ir nanoparticles (NPs) in aqueous solution. Among them, Ibu-Ir NPs demonstrated superior activity against HT-29 cells (IC50 = 1.15 μM), showing 5.6-fold greater potency than free Ir. Mechanistically, Ibu-Ir NPs downregulated cyclooxygenase-2 and topoisomerase I expression, enhancing Ir's therapeutic effect. In HT-29 xenograft models, Ibu-Ir NPs was able to inhibit tumor growth, although the small sample size (n = 3) carries a high risk of statistical errors. This simple yet potent strategy combines anti-inflammatory and anticancer actions, demonstrating significant potential for colorectal cancer therapy.
Insights
Novel nanodrugs combine anti-inflammatory drugs and chemotherapy to create potent nanoparticles for enhanced colorectal cancer therapy, reducing toxicity and improving efficacy.
Area of Science:
- Nanotechnology
- Drug Delivery
- Oncology
Background:
- Self-assembled nanodrug conjugates offer targeted tumor delivery, minimizing systemic toxicity and maximizing therapeutic outcomes.
- Combining hydrophilic and hydrophobic ligands in nanodrugs enhances their tumor-targeting capabilities.
- Nonsteroidal anti-inflammatory drugs (NSAIDs) possess anti-inflammatory properties that may complement anticancer treatments.
Purpose of the Study:
- To synthesize novel amphiphilic NSAID-irinotecan (Ir) conjugates for self-assembly into carrier-free nanoparticles.
- To evaluate the in vitro and in vivo anticancer efficacy of these novel NSAID-Ir nanoparticles.
- To investigate the underlying mechanisms of action for the most potent NSAID-Ir conjugate.
Main Methods:
- Synthesis of four NSAID-Ir conjugates via ester bond formation.
- Characterization of amphiphilic conjugates and their self-assembly into nanoparticles (NPs).
- In vitro cytotoxicity assays against HT-29 cells and in vivo tumor growth inhibition studies in HT-29 xenograft models.
Main Results:
- Amphiphilic NSAID-Ir conjugates successfully self-assembled into carrier-free NPs.
- Ibuprofen-irinotecan (Ibu-Ir) NPs exhibited superior potency against HT-29 cells (5.6-fold greater than free Ir).
- Ibu-Ir NPs demonstrated tumor growth inhibition in xenograft models and downregulated cyclooxygenase-2 and topoisomerase I expression.
Conclusions:
- NSAID-Ir NPs represent a promising strategy for enhanced colorectal cancer therapy.
- The combination of anti-inflammatory and anticancer actions in Ibu-Ir NPs offers significant therapeutic potential.
- This approach highlights the potential of self-assembled nanodrug conjugates for improved cancer treatment.
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