Tropomyosin Receptor Kinase C Targeted Delivery of a Peptidomimetic Ligand-Photosensitizer Conjugate Induces Antitumor Immune Responses Following Photodynamic Therapy

Abstract

Tropomyosin receptor kinase C (TrkC) targeted ligand-photosensitizer construct, IYIY-diiodo-boron-dipyrromethene (IYIY-I2-BODIPY) and its scrambled counterpart YIYI-I2-BODIPY have been prepared. IYIY-I2-BODIPY binds TrkC similar to neurotrophin-3 (NT-3), and NT-3 has been reported to modulate immune responses. Moreover, it could be shown that photodynamic therapy (PDT) elevates antitumor immune responses. This prompted us to investigate the immunological impacts mediated by IYIY-I2-BODIPY in pre- and post-PDT conditions. We demonstrated that IYIY-I2-BODIPY (strong response) and YIYI-I2-BODIPY (weak response) at 10 mg/kg, but not I2-BODIPY control, increased the levels of IL-2, IL-4, IL-6 and IL-17, but decreased the levels of systemic immunoregulatory mediators TGF-β, myeloid-derived suppressor cells and regulatory T-cells. Only IYIY-I2-BODIPY enhanced the IFN-γ+ and IL-17+ T-lymphocytes, and delayed tumor growth (~20% smaller size) in mice when administrated daily for 5 days. All those effects were observed without irradiation; when irradiated (520 nm, 100 J/cm2, 160 mW/cm2) to produce PDT effects (drug-light interval 1 h), IYIY-I2-BODIPY induced stronger responses. Moreover, photoirradiated IYIY-I2-BODIPY treated mice had high levels of effector T-cells compared to controls. Adoptive transfer of immune cells from IYIY-I2-BODIPY-treated survivor mice that were photoirradiated gave significantly delayed tumor growth (~40–50% smaller size) in recipient mice. IYIY-I2-BODIPY alone and in combination with PDT modulates the immune response in such a way that tumor growth is suppressed. Unlike immunosuppressive conventional chemotherapy, IYIY-I2-BODIPY can act as an immune-stimulatory chemotherapeutic agent with potential applications in clinical cancer treatment.

Atorvastatin inhibits pancreatic cancer cells proliferation and invasion likely by suppressing neurotrophin receptor signaling

“…Increasing evidence suggests that dysregulated neurotrophin signaling plays a pivotal role in the development of cancer, including PC (14,15). A recently (17)(18)(19). Thus, neurotrophin signaling is one of the most attractive therapeutic targets in PC.…”

“…A recently published Cancer Cell study found that NGF is overexpressed and promotes accelerated tumor development in PDAC cells, and therapy with a Trk inhibitor in conjunction with gemcitabine increased survival in a PC mouse model ( 16 ). Meanwhile, several clinical studies have indicated that NGF, TrkA, TrkB, TrkC and other neurotrophin signaling members are aberrantly overexpressed in PC samples compared to that in normal adjacent tissues ( 17 - 19 ). Thus, neurotrophin signaling is one of the most attractive therapeutic targets in PC.…”

Exploring BODIPY Derivatives as Singlet Oxygen Photosensitizers for PDT

“…Thus, it has been shown that BODIPY dyes with iodine or bromine atoms covalently linked to the BODIPY core can be promising PDT PSs, as an alternative to the porphyrin-based photosensitizers (8-12,45); Nagano et al (47) firstly reported an iodinated BODIPY for 1 O 2 generation directed to PDT. In the same line, Akkaya (11)(12)(55)(56)(57)(58)(59)(60)(61), Burgess (10,46,62,63), Zhao (8,64) and O´Shea (65), among others (66)(67)(68)(69)(70)(71)(72)(73), have also studied BODIPYs with different halogen substitution patterns for the same purpose.…”

A Photosensitized Singlet Oxygen (1O2) Toolbox for Bio-Organic Applications: Tailoring 1O2 Generation for DNA and Protein Labelling, Targeting and Biosensing

“…C. S. Kue et al also illustrated the immune-stimulatory effect of the IYIY ligand. Thus, the IYIY-I 2 -BODIPY conjugate is not only a targeted PDT agent, but also proved to execute immunomodulation and antitumor activity before photoactivation of the PS, acting as a chemotherapeutic agent [ 275 ]. In 2020, S. Y. Ng et al reported another bivalent ligand (IKIK) connected to a BODIPY, suggesting to actively target the TrkC receptor [ 276 ].…”