Surgical resection of cancer remains an important treatment modality. Despite advances in preoperative imaging, surgery itself is primarily guided by the surgeon’s ability to locate pathology with conventional white light imaging. Fluorescence-guided surgery (FGS) can be used to define tumor location and margins during the procedure. Intraoperative visualization of tumors may not only allow more complete resections but also improve safety by avoiding unnecessary damage to normal tissue which can also reduce operative time and decrease the need for second-look surgeries. A number of new FGS imaging probes have recently been developed, complementing a small but useful number of existing probes. In this review, we describe current and new fluorescent probes that may assist FGS.
Immunogenic cell death (ICD) is a form of cell death that activates an adaptive immune response against dead-cell-associated antigens. Cancer cells killed via ICD can elicit antitumor immunity. ICD is efficiently induced by near-infrared photo-immunotherapy (NIR-PIT) that selectively kills target-cells on which antibody-photoabsorber conjugates bind and are activated by NIR light exposure. Advanced live cell microscopies showed that NIR-PIT caused rapid and irreversible damage to the cell membrane function leading to swelling and bursting, releasing intracellular components due to the influx of water into the cell. The process also induces relocation of ICD bio markers including calreticulin, Hsp70 and Hsp90 to the cell surface and the rapid release of immunogenic signals including ATP and HMGB1 followed by maturation of immature dendritic cells. Thus, NIR-PIT is a therapy that kills tumor cells by ICD, eliciting a host immune response against tumor.
Photochemical
reactions can dramatically alter physical characteristics
of reacted molecules. In this study, we demonstrate that near-infrared
(NIR) light induces an axial ligand-releasing reaction, which dramatically
alters hydrophilicity of a silicon phthalocyanine derivative (IR700)
dye leading to a change in the shape of the conjugate and its propensity
to aggregate in aqueous solution. This photochemical reaction is proposed
as a major mechanism of cell death induced by NIR photoimmunotherapy
(NIR-PIT), which was recently developed as a molecularly targeted
cancer therapy. Once the antibody-IR700 conjugate is bound to its
target, activation by NIR light causes physical changes in the shape
of antibody antigen complexes that are thought to induce physical
stress within the cellular membrane leading to increases in transmembrane
water flow that eventually lead to cell bursting and necrotic cell
death.
De novo NAFLD/NASH after PD is characterized by non-obesity and lack of hyperlipidemia and insulin resistance and is associated with pancreatic exocrine insufficiency. In such patients, intensifying pancreatic enzyme supplementation may be useful.
Current immunotherapies for cancer seek to modulate the balance among different immune cell populations, thereby promoting antitumor immune responses. However, because these are systemic therapies, they often cause treatmentlimiting autoimmune adverse effects. It would be ideal to manipulate the balance between suppressor and effector cells within the tumor without disturbing homeostasis elsewhere in the body. CD4+ regulatory T cells (T regs ) are well-known immunosuppressor cells that play a key role in tumor immunoevasion and have been the target of systemic immunotherapies. We used CD25-targeted near-infrared photoimmunotherapy (NIR-PIT) to selectively deplete T regs , thus activating CD8 T and natural killer cells and restoring local antitumor immunity. This not only resulted in regression of the treated tumor but also induced responses in separate untreated tumors of the same cell line derivation. We conclude that CD25-targeted NIR-PIT causes spatially selective depletion of T regs , thereby providing an alternative approach to cancer immunotherapy.
Near-IR photocaging groups based
on the heptamethine cyanine scaffold
present the opportunity to visualize and then treat diseased tissue
with potent bioactive molecules. Here we describe fundamental chemical
studies that enable biological validation of this approach. Guided
by rational design, including computational analysis, we characterize
the impact of structural alterations on the cyanine uncaging reaction.
A modest change to the ethylenediamine linker (N,N′-dimethyl to N,N′-diethyl) leads to a bathochromic shift in the absorbance
maxima, while decreasing background hydrolysis. Building on these
structure–function relationship studies, we prepare antibody
conjugates that uncage a derivative of duocarmycin, a potent cytotoxic
natural product. The optimal conjugate, CyEt-Pan-Duo, undergoes small
molecule release with 780 nm light, exhibits activity in the picomolar
range, and demonstrates excellent light-to-dark selectivity. Mouse
xenograft studies illustrate that the construct can be imaged in vivo prior to uncaging with an external laser source.
Significant reduction in tumor burden is observed following a single
dose of conjugate and near-IR light. These studies define key chemical
principles that enable the identification of cyanine-based photocages
with enhanced properties for in vivo drug delivery.
Despite significant progress in the clinical application of antibody drug conjugates (ADCs), novel cleavage strategies that provide improved selectivity are still needed. Near-IR light could provide a targetable, biocompatible external stimulus to initiate drug release. Here we report the first approach using near-IR light to cleave a small molecule from a biomacromolecule, which we apply to the problem of ADC linkage. Our method uses a recently developed near-IR uncaging reaction that exploits the photochemical reactivity of C4’-N-dialkylamine heptamethine cyanines. This communication describes the synthesis of bioconjugatable cyanine-small molecule photocages, bioconjugation and 690 nm light-mediated cleavage from the anti-EGFR antibody panitumumab, and initial in vitro and in vivo evaluation. These studies provide the critical chemical underpinning from which to develop this near-IR cleavable linker strategy.
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