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1.
Int J Mol Sci ; 23(10)2022 May 10.
Article in English | MEDLINE | ID: mdl-35628108

ABSTRACT

Cancer and drug-resistant superinfections are common and serious problems afflicting millions worldwide. Photodynamic therapy (PDT) is a successful and clinically approved modality used for the management of many neoplastic and nonmalignant diseases. The combination of the light-activated molecules, so-called photosensitizers (PSs), with an appropriate carrier, is proved to enhance PDT efficacy both in vitro and in vivo. In this paper, we focus on the solvation of several potential chlorin PSs in the 1-octanol/phosphate saline buffer biphasic system, their interaction with non-ionic surfactant Tween 80 and photoinactivation of cancer cells. The chlorin conjugates containing d-galactose and l-arginine fragments are found to have a much stronger affinity towards a lipid-like environment compared to ionic chlorins and form molecular complexes with Tween 80 micelles in water with two modes of binding. The charged macrocyclic PSs are located in the periphery of surfactant micelles near hydrophilic head groups, whereas the d-galactose and l-arginine conjugates are deeper incorporated into the micelle structure occupying positions around the first carbon atoms of the hydrophobic surfactant residue. Our results indicate that both PSs have a pronounced affinity toward the lipid-like environment, leading to their preferential binding to low-density lipoproteins. This and the conjugation of chlorin e6 with the tumor-targeting molecules are found to enhance their accumulation in cancer cells and PDT efficacy.


Subject(s)
Neoplasms , Pulmonary Surfactants , Arginine , Excipients , Galactose , Humans , Lipids , Micelles , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Polysorbates/pharmacology , Porphyrins , Surface-Active Agents/chemistry , Surface-Active Agents/pharmacology
2.
Pharmaceutics ; 15(1)2022 Dec 25.
Article in English | MEDLINE | ID: mdl-36678690

ABSTRACT

Cancer is one of the leading causes of death worldwide. Despite substantial progress in the understanding of tumor biology, and the appearance of new generations of targeted drugs and treatment techniques, the success achieved in this battle, with some notable exceptions, is still only moderate. Photodynamic therapy (PDT) is a successful but still underestimated therapeutic modality for treating many superficial cancers. In this paper, we focus on the extensive investigation of the monocationic chlorin photosensitizer (PS), considered here as a new photosensitizing agent for both antitumor and antimicrobial PDT. This monocationic chlorin PS (McChl) obtained from methylpheophorbide a (MPh) via a two-step procedure is well soluble in water in the physiological temperature range and forms stable complexes with passive carriers. McChl generates singlet oxygen with a good quantum yield in a lipid-like environment and binds mainly to low- and high-density lipoproteins in a vascular system. A comparison of the photodynamic activity of this agent with the activity of the well-established photosensitizer chlorin e6 (Chl e6) clearly indicates that McChl provides a much more efficient photoinactivation of malignant and microbial cells. The pilot PDT treatment of M1 sarcoma-bearing rats with this PS demonstrates its good potential for further preclinical investigations.

3.
J Clin Med ; 11(1)2021 Dec 31.
Article in English | MEDLINE | ID: mdl-35011974

ABSTRACT

Bladder cancer is a common disease with a high recurrence rate. In order to improve the treatment of superficial bladder tumors, we evaluated the efficacy and safety of transurethral resection (TURB) followed by fluorescence diagnosis (FD) and photodynamic therapy (PDT) with chlorin e6 photosensitizers (PSs), viz. "Fotoran e6" and "Fotoditazin". It was found that both PSs generated singlet oxygen and revealed moderate affinity toward the lipid-like compartment. Between November 2018 and October 2020, 12 patients with verified non-muscle invasive bladder cancer (NMIBC) were treated by TURB combined with FD and PDT. Eight patients received "Fotoran e6" intravenously, while four patients received intravesical PSs. The patient ages were between 31 and 79 years, with a median age of 64.5 years (mean 61.3 ± 14.2). The total light dose was 150 J/cm2 for the local irradiation of the tumor bed with a red light at the λ = 660 nm wavelength, and 10-25 J/cm2 were additionally delivered for diffuse irradiation of the entire bladder mucosa. At the median follow-up period of 24 months (mean 24.5 ± 5.4 months, range 16-35 months), 11 patients remained tumor-free. One 79-year-old patient developed a recurrence without progression to the muscle layer. This pilot study shows that the TURB + FD + PDT technique is an effective and safe option for the first-line treatment of superficial bladder tumors.

4.
Int J Biol Macromol ; 145: 244-251, 2020 Feb 15.
Article in English | MEDLINE | ID: mdl-31870869

ABSTRACT

BACKGROUND: The G-quadruplex-forming sequence within the KRAS proto-oncogene P1 promoter is a promising target for anticancer therapy. Porphyrin derivatives are among the most rewarding G-quadruplex binders. They can also behave as photosensitizers. METHODS: Three water-soluble, positively charged porphyrin-like compounds were synthesized and tested for their interaction with the KRAS G-quadruplex by circular dichroism, fluorescence, and molecular docking calculations. For a comparison of ligands binding affinity and selectivity, TMPyP4 was taken as a reference. RESULTS: One out of the three tested compounds proved biological activity and selectivity for G-quadruplex over duplex DNA. It also showed to discriminate between different G-quadruplex topologies, with a preference for the parallel over antiparallel conformation. Molecular docking studies suggested a preferential binding to the 3'-end of the KRAS G-quadruplex driven through π-π stacking interactions. Biological assays also revealed a good photodynamic-induced cytotoxicity on HeLa cells. CONCLUSIONS: The reported results show that these porphyrin-like compounds could actually give the basis for the development of G-quadruplex ligands with effective photodynamic-induced cytotoxicity on cancer cells. GENERAL SIGNIFICANCE: The possibility of obtaining photosensitizers with improved physico-chemical features and able to selectively target G-quadruplexes is a very interesting perspective to develop new therapeutic agents.


Subject(s)
G-Quadruplexes/drug effects , Photosensitizing Agents/pharmacology , Porphyrins/pharmacology , Promoter Regions, Genetic , Proto-Oncogene Proteins p21(ras)/genetics , G-Quadruplexes/radiation effects , HeLa Cells , Humans , Inverted Repeat Sequences , Ligands , Light , Molecular Docking Simulation , Oligonucleotides/chemical synthesis , Photochemotherapy/methods , Photosensitizing Agents/chemical synthesis , Porphyrins/chemical synthesis , Proto-Oncogene Mas , Proto-Oncogene Proteins p21(ras)/metabolism , Solubility , Water
5.
Urol J ; 15(3): 87-91, 2018 05 03.
Article in English | MEDLINE | ID: mdl-29277881

ABSTRACT

PURPOSE: The paper focuses on the relationship of risk factors and metabolic disorders with mineralogical composition of calculi, age and gender of calcium oxalate stone formers. MATERIALS AND METHODS: Stone mineralogical composition, 24 hour biochemistry and pH-profile of urine were examined for sixty four stone formers using powder X-ray diffraction, spectrophotometric and potentiometric techniques. RESULTS: The analysis indicated that 44 % of calculi were composed of pure calcium oxalate monohydrate, whereas other 56 % contained both monohydrate and dihydrate or usually their mixtures with hydroxyl apatite. Hypocitraturia, hypercalciuria and hyperuricosuria were identified as the most frequent disorders. Patients with pure calcium oxalate stones and calcium oxalate mixed with apatite revealed different patterns including age, acid-base balance of urine, calcium, citrate excretion etc.Conclusions: Our results demonstrate that most patients simultaneously reveal several risk factors. The special attention should be paid to normalize the daily citrate, calcium and urate excretion. High risk patients, such as postmenopausal females or stone formers with a high apatite content require a specific metabolic evaluation towards in highlighting abnormalities associated with stone formation.


Subject(s)
Calcium Oxalate/analysis , Kidney Calculi/chemistry , Kidney Calculi/urine , Acid-Base Equilibrium , Adult , Age Factors , Calcium/urine , Citric Acid/urine , Durapatite/analysis , Female , Humans , Hydrogen-Ion Concentration , Hypercalciuria/complications , Hypercalciuria/urine , Kidney Calculi/complications , Male , Middle Aged , Potentiometry , Risk Factors , Spectrophotometry , Uric Acid/urine , Urinalysis , Urine/chemistry , X-Ray Diffraction
6.
J Phys Chem B ; 116(7): 2325-9, 2012 Feb 23.
Article in English | MEDLINE | ID: mdl-22276619

ABSTRACT

We have studied thermodynamics of interaction between the aromatic amino acid L-histidine and glycerol, which is one of the most important stabilizing agents for proteins in water. The pair and triplet interaction parameters have been extracted from enthalpy and solubility data using standard thermodynamic manipulations in a wide temperature range. Our results indicate for the first time that the L-histidine-glycerol pair and triplet interactions are characterized by rather small enthalpy and entropy changes, which do not depend on temperature in either cold or hot water. These temperature-independent enthalpies and entropies of interaction lead to zero heat capacity changes during the amino acid transfer from water to both dilute and rather concentrated aqueous glycerol solutions. We attribute this behavior to a delicate balance between contributions from hydrophobic and hydrophilic fragments in the solute molecules. This unique feature appears to be the major reason that thermodynamics of pair and triplet interactions are nearly identical at standard and physiological temperatures.


Subject(s)
Glycerol/chemistry , Histidine/chemistry , Water/chemistry , Hydrophobic and Hydrophilic Interactions , Models, Molecular , Solubility , Thermodynamics
7.
Urol Res ; 40(3): 205-9, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22089056

ABSTRACT

The flow cell modeling clinical conditions have been used to study the interaction between dilute chemolytic solutions and large calcium oxalate renal stones. The stone treatment with 5% disodium ethylenediaminetetraacetate aqueous solutions or citrate buffer are found not to provide notable disruption of the samples studied. The significant improvement is reached with the mixed compositions containing both natural and synthetic chelating reagents:citrate and ethylenediaminetetraacetate ions as well as an antibiotic. Description of the chemolytic irrigation, numerical results and their possible clinical application are the main topic of the present research.


Subject(s)
Calcium Oxalate/chemistry , Kidney Calculi/chemistry , Electron Probe Microanalysis , Humans , Solubility
8.
J Phys Chem B ; 115(49): 14551-5, 2011 Dec 15.
Article in English | MEDLINE | ID: mdl-21950326

ABSTRACT

This paper focuses on the temperature and length scale dependence of solvation of familiar hydrophobic solutes: tetraalkylammonium ions in highly associated solvents with H-bond networks. Standard enthalpies and heat capacities of solution of symmetrical tetraalkylammonium bromides in formamide (FA) and ethylene glycol (C(2)H(4)(OH)(2)) have been computed using experimental ΔH(m)(sol) values and compared with previously reported enthalpies and heat capacities in pure water. Heat capacities of hydration are found to be large, positive, and increase almost linearly up to tetrapentylammonium bromide. Hydration of tetrahexyl- and tetraheptylammonium bromides is accompanied by much smaller heat capacity changes than would be expected from the length scale dependence observed. The same behavior reveals enthalpies and heat capacities of solute transfer from FA and C(2)H(4)(OH)(2) to water. The results obtained rather indicate that solvation of large tetraalkylammonium ions containing more than twenty carbon atoms is accompanied by much less water orientational ordering than for solutes of a moderate size. It results in smaller fluctuations in the water-water pair energy in a hydration shell and consequently reduces the heat capacity of hydration. The comparison of tetraalkylammonium ion behavior in water and the nonaqueous solvents studied shows that the length scale dependence of solvophobic solvation is strongly pronounced in water but not in nonaqueous media.

9.
J Phys Chem B ; 114(31): 10171-5, 2010 Aug 12.
Article in English | MEDLINE | ID: mdl-20684640

ABSTRACT

We have studied the thermodynamics of the pair interaction between aromatic amino acid-l-histidine and nonelectrolyte denaturing globular proteins-hydrophilic urea (U) and presumably hydrophobic dimethylformamide (DMF) in the temperature range of 288-328 K. Our study does indicate for the first time the anomalous temperature dependence of the enthalpies and entropies of the l-histidine-U and l-histidine-DMF interaction in water, which is consistent with the previously reported results for water-urea (U) and water-U-l-phenylalanine systems. This phenomenon is found to be closely related to the behavior of water, since in all cases, the extrema observed arise in the temperature range of 300-308 K, where the temperature dependence of the heat capacity of pure water passes through the minimum. The amino acid-urea interaction is shown to be accompanied in a wide temperature range by a large negative enthalpy change, which reveals a strong tendency of urea binding with polar and charged groups of proteins.


Subject(s)
Amides/chemistry , Histidine/chemistry , Temperature , Water/chemistry , Dimethylformamide/chemistry , Hydrophobic and Hydrophilic Interactions , Protein Denaturation , Solutions , Urea/chemistry
10.
J Phys Chem B ; 113(28): 9547-50, 2009 Jul 16.
Article in English | MEDLINE | ID: mdl-19537693

ABSTRACT

We have studied how complex formation between calcium and ethylenediaminetetraacetate or citrate ions influences the surface texture and the size of passed oxalate-phosphate renal stones. The four hour concrement treatment by sodium citrate or ethylenediaminetetraacetate aqueous solutions strongly affects the stone texture and provides a mass loss of 6-15%. We have found a significant decrease of the calcium and phosphor content on a concrement surface and formation of appreciable cracks. Our results do indicate that the Ca-complexon interaction can be effectively applied for disrupting some types of renal stones and, especially, residual concrements, which frequently occurs after a surgical operation or an extracorporeal shock-wave lithotripsy. This study provides an additional quantitative physicochemical basis for this slightly invasive therapy.

11.
J Phys Chem B ; 112(7): 2040-4, 2008 Feb 21.
Article in English | MEDLINE | ID: mdl-18232683

ABSTRACT

We have studied the temperature and length scale dependence of the energetics of the pair interaction of well-established hydrophobic solutes tetraalkylammonium bromides with hydrophilic formamide (FA) and hydrophobic hexamethylphosphoric triamide (HMPT). Our results do indicate the anomalous length scale dependence of the tetraalkylammonium cation-amide interaction in water. As the cation size is increased, the unfavorable enthalpy of interaction is increased rather linearly until the maximum is reached, after which there appears to be a reversal of the trend. We believe that this phenomenon arises from the impossibility of water to maintain its H-bond network near large tetraalkylammonium cations that leads to the formation of a somewhat disordered solute hydration shell. The energetic cost for overlapping this shell with the amide hydration shell in water is noticeably smaller than that for tetraalkylammonium cations of a moderated size.

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