Accelerating Cellular Uptake with Unnatural Amino Acid for Inhibiting Immunosuppressive Cancer Cells
Meihui Yi1, Gabriel Ashton-Rickardt1, Weiyi Tan1
1Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA 02453, USA.
Abstract:
Targeting immunosuppressive metastatic cancer cells is a key challenge in therapy. We recently have shown that a rigid-rod aromatic, pBP-NBD, that responds to enzymes and kill immunosuppressive metastatic osteosarcoma (mOS) and castration resistant prostate cancer (CRPC) cells in mimetic bone microenvironment. However, pBP-NBD demonstrated moderate efficacy against CRPC cells. To enhance activity, we incorporated the unnatural amino acid L- or D-4,4'-biphenylalanine (L- or D-BiP) into pBP-NBD, drastically increasing cellular uptake and CRPC inhibition. Specifically, we inserted BiP into pBP-NBD to target mOS (Saos2 and SJSA1) and CRPC (VCaP and PC3) cells with overexpressed phosphatases. Our results show that the D-peptide backbone with an aspartate methyl diester at the C-terminal offers the highest activity against these immunosuppressive mOS and CRPC cells. Importantly, imaging shows that the peptide assemblies almost instantly enter the cells and accumulate primarily within the endoplasmic reticulum of Saos2, SJSA1, and PC3 cells and at the lysosomes of VCaP cells. By using BiP to boost cellular uptake and self-assembly within cancer cells, this work illustrates an unnatural hydrophobic amino acid as a versatile and effective residue to boost endocytosis of synthetic peptides for intracellular self-assembly.
Insights
Researchers enhanced a peptide drug to better target and inhibit immunosuppressive metastatic cancer cells, including osteosarcoma and prostate cancer. The modified peptide shows improved cellular uptake and efficacy, accumulating within cancer cells for enhanced therapeutic potential.
Area of Science:
- Biomaterials Science
- Cancer Biology
- Drug Delivery
Background:
- Targeting immunosuppressive metastatic cancer cells remains a significant therapeutic challenge.
- Previous research developed pBP-NBD, a peptide effective against metastatic osteosarcoma (mOS) but with moderate efficacy against castration-resistant prostate cancer (CRPC).
Purpose of the Study:
- To enhance the efficacy of pBP-NBD against CRPC and mOS cells.
- To investigate the role of unnatural amino acids in improving peptide drug delivery and intracellular accumulation.
Main Methods:
- Incorporation of unnatural amino acids L- or D-4,4'-biphenylalanine (L- or D-BiP) into the pBP-NBD structure.
- Testing the modified peptides against mOS (Saos2, SJSA1) and CRPC (VCaP, PC3) cell lines.
- Cellular uptake and intracellular localization studies using imaging techniques.
Main Results:
- The D-peptide backbone with a C-terminal aspartate methyl diester demonstrated the highest activity against mOS and CRPC cells.
- Incorporation of BiP significantly increased cellular uptake and CRPC inhibition compared to the original pBP-NBD.
- Peptide assemblies rapidly entered cancer cells, accumulating in the endoplasmic reticulum or lysosomes depending on the cell type.
Conclusions:
- Unnatural hydrophobic amino acids like BiP can effectively enhance the endocytosis and intracellular self-assembly of synthetic peptides.
- The modified peptide represents a promising strategy for targeting and treating immunosuppressive metastatic cancers.
- This approach offers a versatile method for improving the delivery and efficacy of peptide-based therapeutics.
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