Promising Photodynamic Therapy Agent Research Articles

Ru(II)-Cyanine Complexes as Promising Photodynamic Photosensitizers for the Treatment of Hypoxic Tumours with Highly Penetrating 770 nm Near-Infrared Light.

Light-activated treatments, such as photodynamic therapy (PDT), provide temporal and spatial control over a specific cytotoxic response by exploiting toxicity differences between irradiated and dark conditions. In this work, a novel strategy for developing near infrared (NIR)-activatable Ru(II) polypyridyl-based photosensitizers (PSs) was successfully developed through the incorporation of symmetric heptamethine cyanine dyes in the metal complex via a phenanthrimidazole ligand. Owing to their strong absorption in the NIR region, the PSs could be efficiently photoactivated with highly penetrating NIR light (770 nm), leading to high photocytotoxicities towards several cancer cell lines under both normoxic and hypoxic conditions. Notably, our lead PS (Ru-Cyn-1), which accumulated in the mitochondria, exhibited a good photocytotoxic activity under challenging low-oxygen concentration (2% O2) upon NIR light irradiation conditions (770 nm), owing to a combination of types I and II PDT mechanism. The fact that the PS Protoporphyrin IX (PpIX), the metabolite of the clinically approved 5-ALA PS, was found inactive under the same challenging conditions positions Ru-Cyn-1 complex as a promising PDT agent for the treatment of deep-seated hypoxic tumours.

PEGylated poly(lactic-co-glycolic acid) nanoparticles doped with molybdenum-iodide nanoclusters as a promising photodynamic therapy agent against ovarian cancer

A photosensitizing nanosystem based on PEGylated PLGA nanoparticles doped with luminescent molybdenum-iodide nanoclusters displays advantageous features for photodynamic therapy of ovarian cancer.

Aptamer-modified carbon dots for enhancement of photodynamic therapy of cancer cells

Carbon dots (CDs) have emerged as promising materials for photodynamic therapy (PDT) because of their intriguing photochemical properties, high stability, and low toxicity. However, achieving accurate delivery of CDs based photosensitizers into tumor sites remains a grand challenge. Herein, AS1411 aptamer, a short oligonucleotide sequence with high binding specificity to tumor cells, was chemically decorated to the surface of Asp-CDs to obtain Asp-CDs@AS1411. The aptamer modified Asp-CDs@AS1411 not only retains the excellent properties of Asp-CDs such as high singlet oxygen quantum yield (up to 50%), bright photoluminescence, and good stability, but also features specific recognition and markedly enhanced phototoxicity (4 times) to tumor cells. These combined attributes make Asp-CDs@AS1411 a promising PDT agent for efficient tumor treatment. More importantly, the reported strategy paves a new avenue for developing high performance PDT materials from surface functionalized CDs featuring high photosensitivity and targeting ability.

Photodynamic therapy of melanoma by blue-light photoactivation of flavin mononucleotide

Melanoma is one of the most aggressive and lethal form of cancer. Photodynamic therapy (PDT) is a clinically approved technique for cancer treatment, including non-melanoma skin cancer. However, the most of conventional photosensitizers are of low efficacy against melanoma due to the possible dark toxicity at high drug concentrations, melanin pigmentation, and induction of anti-oxidant defense mechanisms. In the current research we propose non-toxic flavin mononucleotide (FMN), which is a water-soluble form of riboflavin (vitamin B2) as a promising agent for photodynamic therapy of melanoma. We demonstrated selective accumulation of FMN in melanoma cells in vivo and in vitro in comparison with keratinocytes and fibroblasts. Blue light irradiation with dose 5 J/cm2 of melanoma cells pre-incubated with FMN led to cell death through apoptosis. Thus, the IC50 values of human melanoma A375, Mel IL, and Mel Z cells were in a range of FMN concentration 10–30 µM that can be achieved in tumor tissue under systemic administration. The efficiency of reactive oxygen species (ROS) generation under FMN blue light irradiation was measured in single melanoma cells by a label-free technique using an electrochemical nanoprobe in a real-time control manner. Melanoma xenograft regression in mice was observed as a result of intravenous injection of FMN followed by blue-light irradiation of tumor site. The inhibition of tumor growth was 85–90% within 50 days after PDT treatment.

The Mechanism of Fluorescence Quenching of Protein Photosensitizers Based on miniSOG During Internalization of the HER2 Receptor

The protein photosensitizer miniSOG is a promising agent for photodynamic therapy. The genetically encoded phototoxins 4D5scFv-miniSOG and DARPin-miniSOG specifically bind to the HER2 receptor overexpressed on the surface of cancer cells and promote receptor-mediated internalization of HER2. We show that ingestion of proteins in a complex with the receptor reduces the fluorescent signal of the phototoxic module in endosomes. In order to clarify the mechanism of decrease in the fluorescence intensity of miniSOG-based proteins as they enter a cancer cell during internalization, we analyzed the influence of different factors, including low pH, proteolysis, cofactor reduction, and shielding, on changes in the fluorescence of photosensitizers. Shielding and absorption of miniSOG fluorescence by cell fluorophores, including cytochrome c, were found to contribute significantly to the changes in the fluorescent properties of miniSOG.

Evaluation of nuclear imaging potential and photodynamic therapy efficacy of symmetrical and asymmetrical zinc phthalocyanines

Photodynamic therapy (PDT) is a medical treatment for the removal of target tissues involving the delivery of a photosensitizer agent followed by irradiation with visible light. In the present study, symmetric Zn(II)Pc 1 and asymmetrically substituted Zn(II)Pc 2 were synthesized and examined multifunctional agents for tumor nuclear imaging and PDT potential. The Zn(II)Pc 1 and Zn(II)Pc 2 were radiolabeled with 131I with high efficiency (93.4 ± 1.6% and 91.4 ± 1.6%, respectively). The results of the biodistribution study showed that radiolabeled Zn(II)Pc 1 had high uptake on lung, large intestine, ovary and pancreas. However, the uptake of radiolabeled Zn(II)Pc 2 was statically significant in pancreas and intestine. In PDT studies, EMT6/P (mouse mammary cell) and HeLa (cervical adenocarcinoma cell) with Zn(II)Pc 1 and Zn(II)Pc 2 were exposed to red light at the doses of 10–30 J/cm2. Although PDT activity of Zn(II)Pc 2 in HeLa cell line was determined, Zn(II)Pc 1 showed no phototoxic effect in both cell lines. In conclusion, radiolabeled Zn(II)Pc 1 might be a promising imaging agent for the lung, the ovary pancreas, and the colon tumors. However, radiolabeled Zn(II)Pc 2 might be a promising nuclear imaging agent for the colon and the pancreas tumors and promising PDT agent for cervical tumors.

Combination anticancer therapy activity studies for the complex of hypocrellin A and gallium ion

Combining different treatment modalities is widely employed in oncology to improve the therapeutic response. In this work, we develop a multifunctional complex for co-delivery of the anticancer drug Ga(NO3)3 and the photosensitizer hypocrellin A (HA) as potential dual delivery system for the combination of chemotherapy and photodynamic therapy (PDT). Ga(NO3)3 is used in cancer treatment and is synergistic with other anticancer drugs. Hypocrellin A is a natural photosensitizer, which has been extensively and intensively studied as a promising PDT agent. HA can chelate with gallium ion to form a 1:1 complex. Irradiation of the complex with light of suitable wavelength results in efficient generation of singlet oxygen (1O2). In vitro studies have demonstrated the active uptake of the complex into the cytosol of tumor cells. Viability of cells treated with the complex decreased as compared to free HA or Ga(NO3)3, thus showing a combined effect of both HA and Ga(NO3)3.

Biodistribution of Rhenium Cluster Complex K4[Re6S8(CN)6] in the Body of Laboratory Rats

We studied the biodistribution of luminescent octahedral rhenium cluster complex K4[Re6S8(CN)6], a promising agent for photodynamic therapy. It was shown that rhenium complex [Re6S8(CN)6](4-)is mainly accumulated in the liver, the central organ of metabolism, and can be excreted by the kidneys. The cluster complex was also accumulated in the spleen in significant amount, which makes it a promising agent for creation of preparations for diagnostics and treatment of lymphoproliferative disorders. The mean lethal dose of the cluster complex was 0.38 g/kg.

In Vivo Targeted Deep-Tissue Photodynamic Therapy Based on Near-Infrared Light Triggered Upconversion Nanoconstruct

Two major challenges of current photodynamic therapy (PDT) are the limited tissue penetration of excitation light and poor tumor-selectivity of the photosensitizer (PS). To address these issues, we developed a multifunctional nanoconstruct consisting of upconversion nanoparticles (UCNPs) that transform near-infrared (NIR) light to visible light and a photosensitizer zinc(II) phthalocyanine (ZnPc). Folate-modified amphiphilic chitosan (FASOC) was coated on the surface of UCNPs to anchor the ZnPc close to the UCNPs, thereby facilitating resonance energy transfer from UCNPs to ZnPc. Confocal microscopy and NIR small animal imaging demonstrated the enhanced tumor-selectivity of the nanoconstructs to cancer cells that overexpressed folate receptor. Reactive oxygen species (ROS) generation in cancer cells under a 1-cm tissue was higher upon excitation of UCNPs with the 980 nm light than that with 660 nm irradiation. In vivo PDT treatments for deep-seated tumors demonstrated that NIR light-triggered PDT based on the nanoconstructs possessed remarkable therapeutic efficacy with tumor inhibition ratio up to 50% compared with conventional visible light-activated PDT with a noticeable reduced tumor inhibition ratio of 18%. These results indicate that the multifunctional nanoconstruct is a promising PDT agent for deep-seated tumor treatment and demonstrate a new paradigm for enhancing PDT efficacy.

Oxovanadium(iv) based hypocrellin B complexes with enhanced photodynamic activity

Hypocrellin B (HB), a naturally occurring photosensitizer, has been extensively and intensively studied as a promising photodynamic therapy (PDT) agent. In this work, three new oxovanadium(IV) complexes were designed and synthesized with HB as a bridging ligand and phen (1,10-phenanthroline, complex 1), tmp (3,4,7,8-tetramethyl-1,10-phenanthroline, complex 2) and dpq (dipyrido[3,2-f:2'3'-h]quinoxaline, complex 3) as terminal ligands. The use of a diimine terminal ligand avoids the formation of polymeric complexes and ensures the three VO(2+)-HB complexes possess a definite molecular formula and molecular weight to meet the single component requirement for an ideal PDT agent. Compared to HB, the VO(2+)-HB complexes exhibit improved water solubility, enhanced absorptivity in the phototherapeutic window, increased binding affinity toward dsDNA, and similar singlet oxygen quantum yield, therefore advanced DNA photocleavage activity. Both the DNA binding constants and photo nuclease activities of the complexes follow the order 2 (tmp) > 3 (dpq) > 1 (phen), demonstrating the importance of the binding affinity to biomolecules, which improves the bioavailability of reactive oxygen species. Our work opens a new avenue for the development of HB-based PDT agents.

Cellular Changes After Photodynamic Therapy on HEp-2 Cells Using the New ZnPcBr8Phthalocyanine

This study investigated the effects of photodynamic therapy (PDT) by using the new photosensitizer Octal-Bromide Zinc Phthalocyanine (ZnPcBr(8)) on the nucleus, mitochondria, and cytoskeleton of HEp-2 cells. PDT has been widely used as a therapeutic method for tumor-selective treatment and for other diseases. The therapy requires a photosensitizer, molecular oxygen, and visible light. Different studies have demonstrated that cellular organelles are potential targets for PDT, and the results are dependent on the photosensitizer used in the treatment. In this study, we investigated changes in the nucleus, mitochondria, and cytoskeleton of HEp-2 cells after PDT with the new ZnPcBr(8) phthalocyanine. HEp-2 cells were cultivated under standard conditions, and then incubated with ZnPcBr(8) (1 micromol/L) for 1 h, and subsequently irradiated with a diode laser light (676 nm, 30 mW, 4.5 J/cm(2)). The cells were further cultured for 1 and 24 h at 37 degrees C in a 5% CO(2) and analyzed with fluorescence microscopy by using specific probes for the investigated organelles. Before PDT, the photosensitizer showed a cytoplasmic diffuse distribution. After PDT, cells showed multinucleation, a punctuated mitochondrial distribution in the perinuclear region, and cellular retraction due to the cytoskeleton changes. All those cellular alterations disrupted homeostasis, contributing to cellular death, which is the major goal of PDT. Based on our results and the characteristics of the new ZnPcBr(8) phthalocyanine, mechanistic and biochemical studies must be performed, but it is tempting to consider the chemical as a promising agent for PDT.