Abstract
For effective targeted therapy of cancer with chemotherapy-loaded nanoparticles (NPs), antigens that are selective for cancer cells should be targeted to minimise off-tumour toxicity. Human leukocyte antigens (HLAs) are attractive cancer targets as they can present peptides from tumour-selective proteins on the cell surface, which can be recognised by T cells via T cell receptors (TCRs). In this study, docetaxel-loaded polymeric NPs were conjugated to recombinant affinity-enhanced TCRs to target breast cancer cells presenting a tumour-selective peptide-HLA complex. The TCR-conjugated nanoparticles enabled enhanced delivery of docetaxel and induced cell death through tumour-specific peptide-HLA targeting. These in vitro data demonstrate the potential of targeting tumour-restricted peptide-HLA epitopes using high affinity TCR-conjugated nanoparticles, representing a novel treatment strategy to deliver therapeutic drugs specifically to cancer cells.
Highlights
The goal of targeted cancer therapy is to eliminate tumour cells minimising off-target effects in healthy tissues
We have previously developed maleimide-functionalised polymeric NPs using a single emulsion-solvent evaporation approach and showed that free thiol ligands may be site-selectively coupled to their surface in a highly efficient manner.[21]
In accordance with this methodology, a blend of poly(lactic-co-glycolic acid) (PLGA) 502H and PEG-PLGA-maleimide polymers was dissolved with a drug or fluorescent marker into an organic solvent, which was subsequently emulsified to produce a loaded NP suspension
Summary
The goal of targeted cancer therapy is to eliminate tumour cells minimising off-target effects in healthy tissues. Cell surface or intracellular proteins found in hyperactive prosurvival pathways are chosen as potential candidates for pharmacological targeting.[1] One method of targeting these pathways is via the human leukocyte antigens (HLAs), as these molecules present protein fragments at the cell surface (normally 8–11 amino acid peptides) that represent the entire cellular proteome.[2,3] peptide-HLA ( pHLA) complexes presenting unique or dysregulated tumour proteins can be targeted using tumour-specific, or tumour-selective approaches. The natural ligand of pHLA is the T cell receptor (TCR), the primary antigen receptor expressed on the surface of T cells that governs T cell activation and can lead to killing of target cells.[4] The ability of the TCR to recognise disease-associated pHLA, including tumour associated epitopes, has led to the
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