NIR Photodynamic Destruction of PDAC and HNSCC Nodules Using Triple-Receptor-Targeted Photoimmuno-Nanoconjugates: Targeting Heterogeneity in Cancer

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.

Photosensitizer-Functionalized Nanocomposites for Light-Activated Cancer Theranostics

“…The second generation PSs is purer in a chemical sense and offer high quantum yields for the triplet state generation and ROS formation. A group led by Hasan has done a significant number of studies relating to the combination of PDT with other forms of cancer treatment methods [16,17]. Though it is very hard to anticipate the efficacy of both types of PSs, the second generation PSs have still been found to be more reliable in complex biological environments.…”

Progress in Nanocarriers Codelivery System to Enhance the Anticancer Effect of Photodynamic Therapy

“…Nevertheless, single-receptor targeted therapy may cause tumor subsets with low receptor expression to evade treatment and thus fail to completely ablate tumors. Hasan T [141] further constructs a triple recep- Photoimmunotherapy is a tumor-targeting therapy using specific antibodies to tumorassociated receptors chemically coupled with PSs, which is more accurate than conventional PDT and is suitable for tumors at sensitive anatomical sites. Hasan T [140] coupled epidermal growth factor receptor (EGFR) monoclonal antibody Cetuximab with benzoporphyrin derivative for pancreatic ductal adenocarcinoma treatment.…”

Biomimetic Nanotechnology: A Natural Path Forward for Tumor-Selective and Tumor-Specific NIR Activable Photonanomedicines

“…Comprehensively capturing such tumor heterogeneity and accurately recapitulating it within bPNMs, which are capable of homotypic recognition of diverse tumor cell subpopulations, will undoubtedly prove to be the most challenging hurdle in the path to clinical translation. While we have shown that heterogeneity targeting by synthetic, triple receptor-specific PNMs is achievable in vitro, preparing bPNMs with that degree of control over specificity for diverse heterogenous receptors will prove to be problematic in the clinic [ 109 ]. It may, however, be the case that the future of bPNMs which are capable of both tumor-selective delivery and tumor-specific homotypic recognition is not in the use of natural cancer cell membrane coatings.…”