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Intracellular CXCR4⁺ cell targeting with T22-empowered protein-only nanoparticles
Ugutz Unzueta1, María Virtudes Céspedes, Neus Ferrer-Miralles
1Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
Background:
Cell-targeting peptides or proteins are appealing tools in nanomedicine and innovative medicines because they increase the local drug concentration and reduce potential side effects. CXC chemokine receptor 4 (CXCR4) is a cell surface marker associated with several severe human pathologies, including colorectal cancer, for which intracellular targeting agents are currently missing.
Results:
Four different peptides that bind CXCR4 were tested for their ability to internalize a green fluorescent protein-based reporter nanoparticle into CXCR4⁺ cells. Among them, only the 18 mer peptide T22, an engineered segment derivative of polyphemusin II from the horseshoe crab, efficiently penetrated target cells via a rapid, receptor-specific endosomal route. This resulted in accumulation of the reporter nanoparticle in a fully fluorescent and stable form in the perinuclear region of the target cells, without toxicity either in cell culture or in an in vivo model of metastatic colorectal cancer.
Conclusion:
Given the urgent demand for targeting agents in the research, diagnosis, and treatment of CXCR4-linked diseases, including colorectal cancer and human immunodeficiency virus infection, T22 appears to be a promising tag for the intracellular delivery of protein drugs, nanoparticles, and imaging agents.
Insights
The peptide T22 effectively delivers nanoparticles into CXCR4-expressing colorectal cancer cells, accumulating in the perinuclear region without toxicity. This shows promise for targeted cancer therapy and diagnostics.
Area of Science:
- Nanomedicine
- Molecular Targeting
- Biotechnology
Background:
- Cell-targeting peptides and proteins enhance drug delivery and reduce side effects.
- CXC chemokine receptor 4 (CXCR4) is implicated in severe pathologies like colorectal cancer.
- Intracellular targeting agents for CXCR4-positive cancers are currently lacking.
Purpose of the Study:
- To evaluate the potential of cell-targeting peptides for intracellular delivery.
- To identify peptides capable of internalizing nanoparticles into CXCR4-expressing cells.
- To assess the efficacy and safety of T22 peptide for targeted nanomedicine.
Main Methods:
- Four peptides binding CXCR4 were tested for nanoparticle internalization.
- Green fluorescent protein-based reporter nanoparticles were used.
- Cellular uptake, intracellular localization, and toxicity were assessed in vitro and in vivo.
Main Results:
- The T22 peptide, derived from polyphemusin II, efficiently internalized nanoparticles into CXCR4+ cells.
- Internalization occurred via a rapid, receptor-specific endosomal pathway.
- Nanoparticles accumulated in the perinuclear region, showing fluorescence and stability without toxicity.
Conclusions:
- T22 peptide is a promising tool for intracellular delivery of nanoparticles and protein drugs.
- It facilitates targeted delivery for research, diagnosis, and treatment of CXCR4-linked diseases.
- Potential applications include colorectal cancer and HIV infection therapies.
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