Abstract
Receptor heterogeneity in cancer is a major limitation of molecular targeting for cancer therapeutics. Single-receptor-targeted treatment exerts selection pressures that result in treatment escape for low-receptor-expressing tumor subpopulations. To overcome this potential for heterogeneity-driven resistance to molecular targeted photodynamic therapy (PDT), we present for the first time a triple-receptor-targeted photoimmuno-nanoconjugate (TR-PIN) platform. TR-PIN functionalization with cetuximab, holo-transferrin, and trastuzumab conferred specificity for epidermal growth factor receptor (EGFR), transferrin receptor (TfR), and human epidermal growth factor receptor 2 (HER-2), respectively. The TR-PINs exhibited up to a 24-fold improvement in cancer cell binding compared with EGFR-specific cetuximab-targeted PINs (Cet-PINs) in low-EGFR-expressing cell lines. Photodestruction using TR-PINs was significantly higher than the monotargeted Cet-PINs in heterocellular 3D in vitro models of heterogeneous pancreatic ductal adenocarcinoma (PDAC; MIA PaCa-2 cells) and heterogeneous head and neck squamous cell carcinoma (HNSCC, SCC9 cells) containing low-EGFR-expressing T47D (high TfR) or SKOV-3 (high HER-2) cells. Through their capacity for multiple tumor target recognition, TR-PINs can serve as a unique and amenable platform for the effective photodynamic eradication of diverse tumor subpopulations in heterogeneous cancers to mitigate escape for more complete and durable treatment responses.
Highlights
Photodynamic therapy (PDT) is a unique spatiotemporally controlled treatment modality that utilizes the simultaneous presence of light, a photosensitizer (PS), and oxygen
We have developed NIR-activable, triple-receptor-targeted photoimmunonanoconjugates (TR-PINs) with three ligands, cetuximab, holo-transferrin, and trastuzumab, conjugated to a single photosensitizing nanoconstruct to simultaneously target heterogeneous tumor cell subpopulations with differential expression levels of epidermal growth factor receptor (EGFR), transferrin receptor (TfR), and human epidermal growth factor receptor 2 (HER-2)
We have recently shown for the first time that our chemically tuned NIR light-activated Cet-PINs targeted to a single receptor, EGFR, selectively binding, permeating, and destroying tumor cells in a 3D heterocellular pancreatic ductal adenocarcinoma (PDAC) model more efficiently than untargeted-PSNs [65]
Summary
Photodynamic therapy (PDT) is a unique spatiotemporally controlled treatment modality that utilizes the simultaneous presence of light, a photosensitizer (PS), and oxygen. We have developed NIR-activable, triple-receptor-targeted photoimmunonanoconjugates (TR-PINs) with three ligands, cetuximab (anti-EGFR mAb), holo-transferrin (natural ligand for TfR), and trastuzumab (anti-HER-2 mAb), conjugated to a single photosensitizing nanoconstruct to simultaneously target heterogeneous tumor cell subpopulations with differential expression levels of EGFR, TfR, and HER-2. These TR-PINs carrying a lipid-anchored derivative of the PS benzoporphyrin derivative (BPD-PC) are proposed to increase the specificity and overall completeness of PDT response in tumors with heterogeneous receptor expression. By targeting three receptors simultaneously, a diverse range of cancers from multiple tissue origins and genetic backgrounds may be effectively treated and resistance to monotargeted treatments that arise from receptor heterogeneity can be mitigated
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