Photoactivatable Drugs Research Articles

Unraveling Light-Activated Insulin Action in Regulating Blood Glucose: New Photoactivatable Insight as a Novel Modality in Diabetes Management.

Diabetes, particularly type 2 diabetes (T2D), is the main component of metabolic syndrome. It is highly prevalent and has drastically increased with sedentary lifestyles, notably behaviors linked to ease of access and minimal physical activity. Central to this condition is insulin, which plays a pivotal role in regulating glucose levels in the body by aiding glucose uptake and storage in cells, and what happens to diabetes? In diabetes, there is a disruption and malfunction in insulin regulation. Despite numerous efforts, effectively addressing diabetes remains a challenge. This article explores the potential of photoactivatable drugs in diabetes treatment, with a focus on light-activated insulin. We discuss its advantages and significant implications. This article is expected to enrich the existing literature substantially, offering a comprehensive analysis of potential strategies for improving diabetes management. With its minimal physical intrusion, light-activated insulin promises to improve patient comfort and treatment adherence. It offers precise regulation and localized impact, potentially mitigating the risks associated with conventional diabetes treatments. Additionally, light-activated insulin is capable of explicitly targeting RNA and epigenetic factors. This innovative approach may pave the way for more personalized and effective diabetes treatments, addressing not only the symptoms but also the underlying biological causes of the disease. The advancement of light-activated insulin could revolutionize diabetes management. This study represents a pioneering introduction to this novel modality for diabetes management.

In vivo photopharmacology with a caged mu opioid receptor agonist drives rapid changes in behavior.

Photoactivatable drugs and peptides can drive quantitative studies into receptor signaling with high spatiotemporal precision, yet few are compatible with behavioral studies in mammals. We developed CNV-Y-DAMGO-a caged derivative of the mu opioid receptor-selective peptide agonist DAMGO. Photoactivation in the mouse ventral tegmental area produced an opioid-dependent increase in locomotion within seconds of illumination. These results demonstrate the power of in vivo photopharmacology for dynamic studies into animal behavior.

In vivo spatiotemporal control of voltage-gated ion channels by using photoactivatable peptidic toxins

Photoactivatable drugs targeting ligand-gated ion channels open up new opportunities for light-guided therapeutic interventions. Photoactivable toxins targeting ion channels have the potential to control excitable cell activities with low invasiveness and high spatiotemporal precision. As proof-of-concept, we develop HwTxIV-Nvoc, a UV light-cleavable and photoactivatable peptide that targets voltage-gated sodium (NaV) channels and validate its activity in vitro in HEK293 cells, ex vivo in brain slices and in vivo on mice neuromuscular junctions. We find that HwTxIV-Nvoc enables precise spatiotemporal control of neuronal NaV channel function under all conditions tested. By creating multiple photoactivatable toxins, we demonstrate the broad applicability of this toxin-photoactivation technology.

Inhibition of the HIF-1 Survival Pathway as a Strategy to Augment Photodynamic Therapy Efficacy.

Photodynamic therapy (PDT) is a non-to-minimally invasive treatment modality that utilizes photoactivatable drugs called photosensitizers to disrupt tumors with locally photoproduced reactive oxygen species (ROS). Photosensitizer activation by light results in hyperoxidative stress and subsequent tumor cell death, vascular shutdown and hypoxia, and an antitumor immune response. However, sublethally afflicted tumor cells initiate several survival mechanisms that account for decreased PDT efficacy. The hypoxia inducible factor 1 (HIF-1) pathway is one of the most effective cell survival pathways that contributes to cell recovery from PDT-induced damage. Several hundred target genes of the HIF-1 heterodimeric complex collectively mediate processes that are involved in tumor cell survival directly and indirectly (e.g., vascularization, glucose metabolism, proliferation, and metastasis). The broad spectrum of biological ramifications culminating from the activation of HIF-1 target genes reflects the importance of HIF-1 in the context of therapeutic recalcitrance. This chapter elaborates on the involvement of HIF-1 in cancer biology, the hypoxic response mechanisms, and the role of HIF-1 in PDT. An overview of inhibitors that either directly or indirectly impede HIF-1-mediated survival signaling is provided. The inhibitors may be used as pharmacological adjuvants in combination with PDT to augment therapeutic efficacy.

Radionuclides transform chemotherapeutics into phototherapeutics for precise treatment of disseminated cancer

Most cancer patients succumb to disseminated disease because conventional systemic therapies lack spatiotemporal control of their toxic effects in vivo, particularly in a complicated milieu such as bone marrow where progenitor stem cells reside. Here, we demonstrate the treatment of disseminated cancer by photoactivatable drugs using radiopharmaceuticals. An orthogonal-targeting strategy and a contact-facilitated nanomicelle technology enabled highly selective delivery and co-localization of titanocene and radiolabelled fluorodeoxyglucose in disseminated multiple myeloma cells. Selective ablation of the cancer cells was achieved without significant off-target toxicity to the resident stem cells. Genomic, proteomic and multimodal imaging analyses revealed that the downregulation of CD49d, one of the dimeric protein targets of the nanomicelles, caused therapy resistance in small clusters of cancer cells. Similar treatment of a highly metastatic breast cancer model using human serum albumin-titanocene formulation significantly inhibited cancer growth. This strategy expands the use of phototherapy for treating previously inaccessible metastatic disease.

Tuning the Optical Properties of Phenanthriplatin: Towards New Photoactivatable Analogues

AbstractThe activity of traditional bifunctional platinum‐based drugs is based on a double binding attack of DNA strands that eventually damages the genetic code. Unfortunately, such therapy comes with severe side effects, which drastically limit its efficiency and more importantly, its large‐scale applicability. One emerging alternative is the use of monofunctional platinum complexes based on phenanthriplatin, a new molecule that develops a potent toxicity in tumorous cells by reacting with one DNA base only. Herein, we use theoretical tools to assess the optical properties of phenanthriplatin as well as a series of analogues in an effort to pave the way to their use in photoactivated chemotherapy. In a first step, the absorption signatures of both isolated and DNA‐embedded drugs are predicted through ab initio calculations. Two nitro derivatives are shown to activate a charge transfer from the DNA to the drug and might consequently initiate a cascade of photodamage events. In a second step, we performed molecular dynamics simulations that reveal that such structural change is enough to perturb the DNA‐binding mode. The biological implications of these results in the framework of the design of novel photoactivatable drugs are discussed.

Photooxidation of DNA as a key step in the cytotoxicity of photochromic diarylethenes

The unique photochemistry of diarylethene dyes can be tuned to design photoactivatable drugs. However, their biological mechanism of action has not yet been determined but tentatively ascribed to photoinduced effects on DNA. Herein, we performed theoretical simulations to provide comprehensive insights into the cell death that occurs after the irradiation of diarylethenes-dosed tissues. It is shown that diarylethenes intercalate between DNA base pairs only if the central ring is closed, while two possible pathways might be envisioned for such DNA-photochrome adducts: (i) the use of visible light to open the core ring and release the diarylethene without damaging DNA; or (ii) to produce a degradation of the DNA upon 300–400 nm light radiation. The latter photodamage is characterized by a large charge transfer in the DNA→ diarylethene direction. The described computational protocol might be used to open up new synthetic routes for diarylethenes with clinical applications, e.g., by screening electroacceptor substituent groups to optimize the rates of radiation-induced damage to DNA.

Rapid screening of photoactivatable metallodrugs: photonic crystal fibre microflow reactor coupled to ESI mass spectrometry.

We explore the efficacy of a hyphenated photonic crystal fibre microflow reactor - high-resolution mass spectrometer system as a method for screening the activity of potential new photoactivatable drugs. The use of light to activate drugs is an area of current development as it offers the possibility of reduced side effects due to improved spatial and temporal targeting and novel mechanisms of anticancer activity. The di-nuclear ruthenium complex [{(η6-indan)RuCl}2(μ-2,3-dpp)](PF6)2, previously studied by Magennis et al. (Inorg. Chem., 2007, 46, 5059) is used as a model drug to compare the system to standard irradiation techniques. The photodecomposition pathways using blue light radiation are the same for PCF and conventional cuvette methods. Reactions in the presence of small biomolecules 5'-guanosine monophosphate (5'-GMP), 5'-adenosine monophosphate (5'-AMP), l-cysteine (l-Cys) and glutathione (γ-l-glutamyl-l-cysteinyl-glycine, GSH) were studied. The complex was found to bind to nucleobases in the dark and this binding increased upon irradiation with 488 nm light, forming the adducts [(η6-indan)Ru2(μ-2,3-dpp) + 5'-GMP]2+ and [(η6-indan)Ru + (5'-AMP)]+. These findings are consistent with studies using conventional methods. The dinuclear complex also binds strongly to GSH after irradiation, a possible explanation for its lack of potency in cell line testing. The use of the PCF-MS system dramatically reduced the sample volume required and reduced the irradiation time by four orders of magnitude from 14 hours to 12 seconds. However, the reduced sample volume also results in a reduced MS signal intensity. The dead time of the combined system is 15 min, limited by the intrinsic dead volume of the HR-MS.

On the use of diarylmaleimide derivatives in biological contexts: An investigation of the photochromic properties in aqueous solution

A series of photochromic diarylmaleimide derivatives has been synthesized and studied with respect to the photochromic properties in aqueous solution. The main rationale is to investigate if these compounds could be used as photoswitchable units in biological contexts, motivated by the fact that the diarylmaleimide structural motif is identified in many pharmacophores. Thus, photoswitchable variants of this class of compounds could be very useful in the quest for photoactivatable drugs. The photoinduced cyclization reaction (colorization) is suppressed in solvents of high polarity, whereas the ring-opening reaction (decolorization) still occurs with high efficiency. The photochromically active anti-parallel conformer of the open form is more abundant in the asymmetrically substituted derivatives, which in turn favors the formation of the closed isomeric form. The rates of the thermal isomerization reactions have also been assessed, together with the resistance toward thermal degradation. Here it was observed that the maleimide derived compounds were not susceptible to the thermally driven reactions (hydrolysis and isomerization).

Release of Photoactivatable Drugs from Plasmonic Nanoparticles for Targeted Cancer Therapy

Chemotherapy is an important modality in cancer treatment. The major challenges of recent works are to improve drug loading, increase selectivity to target cells, and control the precise release of drugs. In the present study, we devised a smart drug carrier, an aptamer/hairpin DNA-gold nanoparticle (apt/hp-Au NP) conjugate for targeted delivery of drugs. The DNA aptamer sgc8c, which possesses strong affinity for protein tyrosine kinase 7 (PTK7), abundantly expressed on the surface of CCRF-CEM (T-cell acute lymphoblastic leukemia) cells, was assembled onto the surface of Au NPs. The repeated d(CGATCG) sequence within the hpDNA on the Au NP surface was used for the loading of the anticancer drug doxorubicin (Dox). After optimization, 25 (±3) sgc8c and 305 (±9) Dox molecules were successfully loaded onto the AuNP (13 nm) surface. The binding capability of apt/hp-Au NP conjugates toward targeted cells was investigated by flow cytometry and atomic absorption spectroscopy, which showed that the aptamer-functionalized nanoconjugates were selective for targeting of cancer cells. A cell toxicity (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, MTT) assay also demonstrated that these drug-loaded nanoconjugates could kill targeted cancer cells more effectively than nontargeted (control) cells. Most importantly, when illuminated with plasmon-resonant light (532 nm), Dox:nanoconjugates displayed enhanced antitumor efficacy with few side effects. The marked release of Dox from these nanoconjugates in living cells was monitored by increasing fluorescence signals upon light exposure. In vitro studies confirmed that aptamer-functionalized hp-Au NPs can be used as carriers for targeted delivery of drugs with remote control capability by laser irradiation with high spatial/temporal resolution.

Specific molecular and cellular events induced by irradiated X-ray photoactivatable drugs raise the problem of co-toxicities: particular consequences for anti-cancer synchrotron therapy

Synchrotrons are capable of producing intense low-energy X-rays that enable the photoactivation of high-Z elements. Photoactivation therapy (PAT) consists of loading tumors with photoactivatable drugs and thereafter irradiating them at an energy, generally close to the K-edge of the element, that enhances the photoelectric effect. To date, three major photoactivatable elements are used in PAT: platinum (cisplatin and carboplatin), iodine (iodinated contrast agents and iododeoxyuridine) and gadolinium (motexafin gadolinium). However, the molecular and cellular events specific to PAT and the radiobiological properties of these photoactivatable drugs are still misknown. Here, it is examined how standard and synchrotron X-rays combined with photoactivatable drugs impact on the cellular response of human endothelial cells. These findings suggest that the radiolysis products of the photoactivatable drugs may participate in the synergetic effects of PAT by increasing the severity of radiation-induced DNA double-strand breaks. Interestingly, subpopulation of highly damaged cells was found to be a cellular pattern specific to PAT. The data show that the efficiency of emerging anti-cancer modalities involving synchrotron photoactivation strongly depends on the choice of photoactivatable drugs, and important series of experiments are required to secure their clinical transfer before applying to humans.

Targetable photoactivatable drugs

The photodynamic activity of photosensitizer chlorin e6 and its targeted or nontargeted polymeric derivatives were evaluated on the human hepatocarcinoma cell line PLC/PRF/5 (targeting structure was galactosamine) or on mouse T splenocytes (targeting structures were anti Thy 1.2 antibodies). It was found that the targeted conjugate is up to 500 hundred times more phototoxic than its nontargeted counterpart. Photodynamic activity of polymeric chlorin e6 targeted with ATS-A (randomly bound antibody) was detected up to the concentration of 1×10−6m (0.65 µg drug/ml), while photodynamic activity of polymeric chlorin e6 targeted with ATS-C (oriented binding of antibody via their Fc part) was detected up to the concentration of 1×10−8m (0.0065 µg drug/ml). The final photodynamic effect was dependent on the time and temperature of incubation and on the time of irradiation.

Targetable photoactivatable polymeric drugs

The design of targetable polymeric photoactivatable drugs based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers is described. Two types of conjugates have been synthesized: (a) HPMA copolymer-galactosamine-chlorin e 6 conjugates; and (b) HPMA copolymer-anti-Thy 1.2 antibody-chlorin e 6 conjugates. Their photodynamic activity was evaluated in vitro. The conjugate containing galactosamine as the targeting moiety was tested on a human hepatoma cell line (PLC/PRF/5; Alexander cells) containing the asialoglycoprotein receptor. It was shown that the targetable conjugate was more active in vitro when compared with an HPMA copolymer-chlorin e 6 conjugate. The photodynamic activity of two HPMA copolymer-anti-Thy 1.2 antibody-chlorin e 6 conjugates was evaluated towards mouse splenocytes in vitro. They differ in the method of antibody binding. One contained anti-Thy 1.2 antibodies bound via N ϵ-amino groups of lysine residues, the other contained anti-Thy 1.2 antibodies bound via oxidized carbohydrate groups. Both targetable conjugates were more biologically active when compared to a nontargetable HPMA copolymer-chlorin e 6 conjugate. The conjugate which contained anti-Thy 1.2 antibodies bound via carbohydrate groups was the most active both in its photodynamic effect on the viability of splenocytes and the suppression of the primary antibody response of mouse splenocytes towards sheep red blood cells in vitro.

Targetable photoactivatable drugs, 2. Synthesis of N‐(2‐hydroxypropyl)methacrylamide copolymeranti‐thy 1.2 antibody‐chlorin e6 conjugates and a preliminary study of their photodynamic effect on mouse splenocytes in vitro

AbstractTwo N‐(2‐hydroxypropyl)methacrylamide (HPMA, 1) copolymer‐chlorin e6‐anti‐Thy 1.2 antibody conjugates were synthesized. They differ in the method of antibody binding. In conjugate 11, the polyclonal anti‐Thy 1.2 antibody was bound via Nϵ‐amino groups of lysine residues. Conjugate 14 contained anti‐Thy‐1.2 antibodies bound via oxidized carbohydrate groups present near the hinge region in the Fc part of the antibody molecule. The photodynamic activity of these conjugates towards mouse splenocytes in vitro was compared with the activity of a nontargetable HPMA copolymer‐chlorin e6 conjugate (15) and free chlorin e6. Whereas free chlorin e6 was cytotoxic both when kept in the dark and when splenocytes were irradiated, the binding of the drug to HPMA copolymers considerably decreased its cytotoxicity in the dark. Conjugates 11 and 14 containing targeting polyclonal anti‐Thy 1.2 antibodies were more biologically active compared to the nontargetable conjugate 15. Conjugate 14, which contained anti‐Thy 1.2 antibodies bound at a specific location was the most active both in its photodynamic effect on viability of splenocytes and/or suppression of the primary antibody response of mouse splenocytes towards sheep red blood cells in vitro. The results demonstrate the importance of the chemistry of antibody binding on the biological activity of targetable polymeric drugs.