Abstract
BackgroundPhotoimmunotherapy involves targeted delivery of photosensitizers via an antibody conjugate (i.e., photoimmunoconjugate, PIC) followed by light activation for selective tumor killing. The trade-off between PIC selectivity and PIC uptake is a major drawback limiting the efficacy of photoimmunotherapy. Despite ample evidence showing that photoimmunotherapy is most effective when combined with chemotherapy, the design of nanocarriers to co-deliver PICs and chemotherapy drugs remains an unmet need. To overcome these challenges, we developed a novel photoimmunoconjugate-nanoliposome (PIC-Nal) comprising of three clinically used agents: anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody cetuximab (Cet), benzoporphyrin derivative (BPD) photosensitizer, and irinotecan (IRI) chemotherapy.ResultsThe BPD photosensitizers were first tethered to Cet at a molar ratio of 6:1 using carbodiimide chemistry to form PICs. Conjugation of PICs onto nanoliposome irinotecan (Nal–IRI) was facilitated by copper-free click chemistry, which resulted in monodispersed PIC–Nal–IRI with an average size of 158.8 ± 15.6 nm. PIC–Nal–IRI is highly selective against EGFR-overexpressing epithelial ovarian cancer cells with 2- to 6-fold less accumulation in low EGFR expressing cells. Successful coupling of PIC onto Nal–IRI enhanced PIC uptake and photoimmunotherapy efficacy by up to 30% in OVCAR-5 cells. Furthermore, PIC–Nal–IRI synergistically reduced cancer viability via a unique three-way mechanism (i.e., EGFR downregulation, mitochondrial depolarization, and DNA damage).ConclusionIt is increasingly evident that the most effective therapies for cancer will involve combination treatments that target multiple non-overlapping pathways while minimizing side effects. Nanotechnology combined with photochemistry provides a unique opportunity to simultaneously deliver and activate multiple drugs that target all major regions of a cancer cell—plasma membrane, cytoplasm, and nucleus. PIC–Nal–IRI offers a promising strategy to overcome the selectivity-uptake trade-off, improve photoimmunotherapy efficacy, and enable multi-tier cancer targeting. Controllable drug compartmentalization, easy surface modification, and high clinical relevance collectively make PIC–Nal–IRI extremely valuable and merits further investigations in living animals.
Highlights
Photoimmunotherapy involves targeted delivery of photosensitizers via an antibody conjugate followed by light activation for selective tumor killing
We previously developed a PIC system that comprises of the U.S Food and Drug Administration (FDA)-approved anti-Epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab (Cet) and a clinically used benzoporphyrin derivative (BPD) photosensitizer to target cancer cells [7,8,9,10,11]
We recently demonstrated that immobilization of PIC onto poly(lactic-co-glycolic acid) (PLGA) nanoparticles could facilitate the indirect endocytosis of high payloads of PIC under limited antibody-receptor binding events, overcoming the persistent challenge of insufficient PIC uptake by cancer cells [10]
Summary
Photoimmunotherapy involves targeted delivery of photosensitizers via an antibody conjugate (i.e., photoimmunoconjugate, PIC) followed by light activation for selective tumor killing. Despite ample evidence showing that photoimmunotherapy is most effective when combined with chemotherapy, the design of nanocarriers to co-deliver PICs and chemotherapy drugs remains an unmet need To overcome these challenges, we developed a novel photoimmunoconjugate-nanoliposome (PIC-Nal) comprising of three clinically used agents: anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody cetuximab (Cet), benzoporphyrin derivative (BPD) photosen‐ sitizer, and irinotecan (IRI) chemotherapy. It is wellestablished that light activation of BPD induces photochemical disruption of the mitochondrial membrane [9], which triggers the release of cytochrome c, a potent initiator of apoptotic cell death [12,13,14] This shifts the balance in the target cells from an anti-apoptotic state to a more pro-apoptotic state, mediating eventual cell death
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