Popov, Alexander Aleksandrovich

Popov A., Suvorov N., Larkina M., Plotnikov E., Varvashenya R., Bodenko V., Yanovich G., Ostroverkhov P., Usachev M., Filonenko E., Belousov M., Grin M.

The use of radiopharmaceuticals for diagnostics in oncology allows for the detection of the disease at an early stage. Among diagnostic radionuclides, 99mTc is a promising isotope that has been used to create several drugs for clinical use. One of the most effective 99mTc chelators is 6-hydrazinylnicotinic acid (HYNIC), which, when combined with various vector molecules, can be used for targeted delivery of radionuclides to tumor tissues. At the same time, it is known that tetrapyrrole macrocycles are capable of selective accumulation in tumors, and thus can be used to target radiopharmaceuticals with 99mTc. In this work, the conjugate of natural chlorin and HYNIC was obtained, and preliminary preclinical studies were carried out on its radiocomplex with 99mTc.

Popov A., Suvorov N., Kornikov A., Ostroverkhov P., Tikhonov S., Pogorilyy V., Demina A., Usachev M., Plotnikova E., Pankratov A., Lepnev L., Safiullina E., Utochnikova V., Milaeva E., Grin M.

Grin M., Ostroverkhov P., Suvorov N., Tikhonov S., Popov A., Shelyagina A., Kirin N., Nichugovskiy A., Usachev M., Bragina N., Plotnikova E., Pankratov A.

Combined therapy is currently a popular method for increasing the efficiency of antitumor treatment. It involves the use of two different tumor treatment methods, namely, chemotherapy and PDT. Combining a cytotoxic agent and a photosensitizer in a single molecule results in a synergistic antitumor effect that overcomes the multiple drug resistance and reduces the therapeutic drug doses. In this work, pyridine-containing natural chlorins were obtained by introducing a pyridine group into 131-[Formula: see text]-(4-aminobutyl)amide of chlorin [Formula: see text] and its bacteriochlorin analogue, [Formula: see text]-propyloxime-[Formula: see text]-propoxybacteriopurinimide as well as [Formula: see text]-aminobacteriopurinimide methyl ester. Moreover, a terpyridine residue was introduced as an external chelating moiety into [Formula: see text]-hydroxypurpurinimide and [Formula: see text]-aminobacteriopurinimide, and platinum complexes of all the above photosensitizers were obtained. The interactions of the latter with DNA were simulated and the lead compound, the platinum complex of pyridine derivative 131-[Formula: see text]-(4-aminobutyl)amide chlorin [Formula: see text], which may become a potential agent for combined photodynamic and chemotherapy in oncology, was selected. The ability of the compounds obtained to manifest photodynamic and chemocytotoxic effects on tumor cells of various genesis was shown.

Grin M., Suvorov N., Ostroverkhov P., Pogorilyy V., Kirin N., Popov A., Sazonova A., Filonenko E.

When conducting combined therapy of malignant neoplasms, treatment methods with various mechanisms of antitumor effects are used, while an additive or even synergistic effect can be realized. Combination treatment regimens are aimed at increasing the efficiency and, above all, at the complete eradication of the tumor, which can be achieved either by suppressing the survival mechanisms in PDT-resistant tumor cells or by pre-attenuation of tumor cells so that they become more susceptible to subsequent PDT. Photodynamic therapy is an approved medical technology for the treatment of various malignant neoplasms, and several precancerous and non-cancer diseases. To date, numerous data have been published on the combined use of PDT with traditional and innovative methods of treatment. This review considers research in this area in recent years.

Nikolaeva M.E., Popov A.A., Nechaev A.V., Mironov A.F.

Ailioaie L.M., Ailioaie C., Litscher G.

Photodynamic therapy (PDT) is an innovative treatment that has recently been approved for clinical use and holds promise for cancer patients. It offers several benefits, such as low systemic toxicity, minimal invasiveness, and the ability to stimulate antitumor immune responses. For certain types of cancer, it has shown positive results with few side effects. However, PDT still faces some challenges, including limited light penetration into deeper tumor tissues, uneven distribution of the photosensitizer (PS) that can also affect healthy cells, and the difficulties posed by the hypoxic tumor microenvironment (TME). In hypoxic conditions, PDT’s effectiveness is reduced due to insufficient production of reactive oxygen species, which limits tumor destruction and can lead to relapse. This review highlights recent advances in photosensitizers and nanotechnologies that are being developed to improve PDT. It focuses on multifunctional nanoplatforms and nanoshuttles that have shown promise in preclinical studies, especially for treating solid tumors. One of the key areas of focus is the development of PSs that specifically target mitochondria to treat deep-seated malignant tumors. New mitochondria-targeting nano-PSs are designed with better water solubility and extended wavelength ranges, allowing them to target tumors more effectively, even in challenging, hypoxic environments. These advancements in PDT are opening new doors for cancer treatment, especially when combined with other therapeutic strategies. Moving forward, research should focus on optimizing PDT, creating more efficient drug delivery systems, and developing smarter PDT platforms. Ultimately, these efforts aim to make PDT a first-choice treatment option for cancer patients.

Goujani S.M., Koopaie M., Safarian F.H., Hakimiha N., Younespour S.

Kumbham S., Md Mahabubur Rahman K., Foster B.A., You Y.

Krylova L.V., Otvagin V.F., Gribova G.P., Kuzmina N.S., Fedotova E.A., Zelepukin I.V., Nyuchev A.V., Kustov A.V., Morshnev P.K., Berezin D.B., Koifman M.O., Vatsadze S.Z., Balalaeva I.V., Fedorov A.Y.

Popov A., Suvorov N., Larkina M., Plotnikov E., Varvashenya R., Bodenko V., Yanovich G., Ostroverkhov P., Usachev M., Filonenko E., Belousov M., Grin M.

The use of radiopharmaceuticals for diagnostics in oncology allows for the detection of the disease at an early stage. Among diagnostic radionuclides, 99mTc is a promising isotope that has been used to create several drugs for clinical use. One of the most effective 99mTc chelators is 6-hydrazinylnicotinic acid (HYNIC), which, when combined with various vector molecules, can be used for targeted delivery of radionuclides to tumor tissues. At the same time, it is known that tetrapyrrole macrocycles are capable of selective accumulation in tumors, and thus can be used to target radiopharmaceuticals with 99mTc. In this work, the conjugate of natural chlorin and HYNIC was obtained, and preliminary preclinical studies were carried out on its radiocomplex with 99mTc.

Das B.

AbstractTransition metal complex‐loaded nanosystems (TMCNs) represent a cutting‐edge platform for stimuli (light, ultrasound)‐responsive cancer therapies. These nanosystems, incorporating metals such as manganese(II), zinc(II), ruthenium(II), rhenium(I), iridium(III), and platinum(IV), significantly enhance the efficacy of light‐activated therapies, including photodynamic therapy (PDT) and photothermal therapy (PTT), as well as ultrasound‐activated treatments like sonodynamic therapy (SDT). TMCNs based on ruthenium(II), rhenium(I), and iridium(III) improve PDT, while manganese(II) and iridium(III) demonstrate exceptional sonosensitizing properties. In PTT, ruthenium(II) and iridium(III)‐based TMCNs efficiently absorb light and generate heat. Emerging synergistic approaches that combine SDT, PTT, PDT, chemotherapy, and immunotherapy are demonstrated to be powerful strategies for precision cancer treatment. Zinc(II), ruthenium(II), iridium(III), and platinum(IV)‐based TMCNs play a critical role in optimizing these therapies, enhancing tumor targeting, and reducing side effects. Furthermore, TMCNs can amplify immunotherapy by inducing immunogenic cell death, thus strengthening the immune response. These advances address key challenges such as tumor hypoxia and therapeutic resistance, opening new possibilities for innovative photosensitizer‐based cancer treatments. This review highlights the latest progress in TMCNs design and applications, demonstrating their potential to revolutionize stimuli‐responsive cancer therapies.

Lafi Z., Matalqah S., Abu-Saleem E., Asha N., Mhaidat H., Asha S., Al-Nashash L., Janabi H.S.

The integration of nanotechnology into cancer treatment has revolutionized chemotherapy, boosted its effectiveness while reduced side effects. Among the various nanotherapeutic approaches, metal–organic frameworks (MOFs) stand out as promising carriers for targeted chemotherapy, with the added benefit of enabling combination therapies. MOFs, composed of metal ions or clusters linked by coordination bonds, tackle critical issues in traditional cancer treatments, such as poor stability, limited efficacy, and severe side effects. Their key advantages include customizable size and shape, diverse compositions, controlled porosity, large surface areas, ease of modification, and biocompatibility. This review highlights recent advancements in the use of MOFs for cancer therapy, showcasing their role in both monotherapies and combination strategies. Additionally, it explores the future potential and challenges of MOF-based platforms in tumor treatment.

Di Z., Shuhe Z., Baoding S., Yihan Z., Guangming J.

To prepare and characterize transferrin (Tf)-modified liposomes (Lipo) encapsulating the photosensitizing agent neoindocyanine green (IR820), and to investigate their effects on breast cancer 4T1 cells as well as in a breast cancer mouse model. Photosensitive liposomes, IR820@Lipo and Tf-IR820@Lipo, were synthesized using thin film dispersion, with encapsulation efficiency assessed via UV detection. The physicochemical properties were analyzed using transmission electron microscopy (TEM) and particle size analysis. Uptake by breast cancer 4T1 cells was evaluated through confocal laser scanning microscopy and flow cytometry, while cell proliferation inhibition was measured using the CCK8 assay. Differences in intracellular fluorescence intensity were utilized to assess drug aggregation in vivo through small animal imaging techniques. The anticancer efficacy and potential side effects of the formulations were examined through pharmacodynamic studies conducted in vivo. The mean particle sizes of IR820@Lipo and Tf-IR820@Lipo were found to be 84.30 ± 15.66 nm and 116.20 ± 14.68 nm respectively, with zeta potentials of −8.21 ± 2.06 mV for IR820@Lipo and −5.23 ± 1.19 mV for Tf-IR820@Lipo; TEM revealed that the liposomes exhibited a spheroid morphology with uniform distribution across samples; encapsulation efficiencies reached 86.38 ± 0.99% for IR820@Lipo and an impressive 93.81 ± 1.06% for Tf-IR820@Lipo; notably, Tf-IR820@Lipo significantly inhibited proliferation while promoting apoptosis of the 4T1 cells upon laser irradiation; reactive oxygen species (ROS) detection indicated enhanced fluorescence intensity within the treated cells under light exposure when utilizing both formulations; in vivo experiments demonstrated tumor accumulation of both IR820@Lipo and Tf-IR820@Lipo, indicating effective tumor targeting within a breast cancer mouse model; pharmacodynamic assessments revealed that Tf-IR820@Lipo exhibited superior inhibitory effects against breast cancer without causing liver or kidney dysfunctions in mice nor presenting significant toxic side effects overall. Given its high targeting capability, potent efficacy, and low toxicity profile, Tf-IR820@Lipo holds promise as a novel therapeutic agent for breast cancer treatment when combined with photodynamic therapy (PDT), potentially offering new avenues for patient management.

Ziental D., Czarczynska-Goslinska B., Wysocki M., Ptaszek M., Sobotta Ł.

Although nearly 30 years have passed since the introduction of the first clinically approved photosensitizer for photodynamic therapy, progress in developing new pharmaceutical formulations remains unsatisfactory. This review highlights that despite years of research, many recurring challenges and issues remain unresolved. The paper includes an analysis of selected essential studies involving aminolevulinic acid and its derivatives, as well as other photosensitizers with potential for development as medical products. Among various possible vehicles, special attention is given to gelatin, alginates, poly(ethylene oxide), polyacrylic acid, and chitosan. The focus is particularly on infectious and cancerous diseases. Key aspects of developing new semi-solid drug forms should prioritize the creation of easily manufacturable and biocompatible preparations for clinical use. At the same time, new formulations should preserve the primary function of photosensitizers, which is the generation of reactive oxygen species capable of destroying pathogenic cells or tumors. Additionally, the use of adjuvant properties of carriers, which can enhance the effectiveness of macrocycles, is emphasized, especially in chitosan-based antibacterial formulations. Current research indicates that many promising dyes and macrocyclic compounds with high potential as photosensitizers in photodynamic therapy remain unexplored in formulation and development work. This review outlines potential new and previously explored pathways for advancing photosensitizers as active pharmaceutical ingredients (APIs).

Demingo M., Lembo A., Petrella G., Gontrani L., Limosani F., Arrigoni G., Carbone M., Cicero D., Tagliatesta P.

Porphyrins belong to a peculiar class of the natural molecules involved in many different biological processes of paramount of importance, starting from the photosynthesis in green plants, passing through the...

Yalazan H., Kantekin H., Durmuş M.

Singh P.P., Sinha S., Gahtori P., Mishra D.N., Pandey G., Srivastava V.

Photodynamic therapy (PDT) is a contemporary, non-invasive therapeutic modality utilised to treat cancers of diverse kinds and locales in addition to non-cancerous disorders. The basic concept of this theory includes the application of a photosensitizer, a substance which develops in diseased tissues and is photosensitive, either locally or systemically. Combining photosensitizers and nanomaterials can both reduce the adverse effects of photodynamic treatment and increase its effectiveness. The combination of PDT with chemotherapy and immunotherapies provides a way in acquiring knowledge of biological mechanism underpinning PDT that offers researchers a broad framework in which to design approaches to enhance the efficacy of the many therapies involved. This review aims to investigate the use, advantages, and potential modifications to improve the anticancer effects of PDT.

Law S.K., Liu C.W., Tong C.W., Au D.C.

Bacterial infections and cancers are important issues in public health around the world. Currently, Western medicine is the most suitable approach when dealing with these issues. “Antibiotics” and “Corticosteroids” are the Western medicines used for bacterial infection. “Chemotherapy drugs”, “surgery”, and “radiotherapy” are common techniques used to treat cancer. These are conventional treatments with many side effects. PDT is a non-invasive and effective therapy for bacterial infection and cancer diseases. Methods: Nine electronic databases, namely WanFang Data, PubMed, Science Direct, Scopus, Web of Science, Springer Link, SciFinder, and China National Knowledge Infrastructure (CNKI), were searched to conduct this literature review, without any regard to language constraints. Studies focusing on the photodynamic actions of hydrogel and Resveratrol were included that evaluated the effect of PDT against bacteria and cancer. All eligible studies were analyzed and summarized in this review. Results: Resveratrol has antibacterial and anticancer effects. It can also act as PS in PDT or adjuvant but has some limitations. This is much better when combined with a hydrogel to enhance the effectiveness of PDT in the fight against bacteria and cancer. Conclusions: Resveratrol combined with hydrogel is possible for PDT treatment in bacteria and cancer. They are compatible and reinforce each other to increase the effectiveness of PDT. However, much more work is required, such as cytotoxicity safety assessments of the human body and further enhancing the effectiveness of PDT in different environments for future investigations.

Kirin N.S., Ostroverkhov P.V., Usachev M.N., Birin K.P., Grin M.A.

Objectives. To synthesize Pt-containing derivatives of natural chlorins as potential agents for the combination therapy in oncology. Platinum compounds are known to occupy an important place as chemotherapeutic agents in the treatment of oncological diseases. However, Pt(II) complexes are highly toxic to the body and are not selectively accumulated in tumor cells. If photodynamic and chemotherapy methods are combined in a single drug, the pigments are responsible for the selectivity of conjugate accumulation in the tumor, while a chemotherapeutic agent based on Pt(II) complexes is responsible for the cytotoxic effect on tumor cells. This will not affect healthy cells and thereby minimize the systemic toxicity of the drug to the body.Methods. Methods for the synthesis of pyridine-containing derivatives of natural chlorins and their metal complexes for use as potential binary agents in oncology were applied. As part of the study, the structures of the compounds obtained were confirmed by mass spectrometry, nuclear magnetic resonance spectroscopy, ultraviolet spectroscopy, and high-resolution chromatography-mass spectrometry. Preparative methods, including thin-layer and column chromatography, centrifugation and recrystallization, were used to isolate and purify the compounds obtained.Results. Platinum(II) complexes of pyridine-containing derivatives of natural chlorins were obtained for application in combination therapy in oncology. The schemes for synthesizing the target photosensitizers were optimized, in order to increase the yields and for subsequent transfer to industrial sites.Conclusions. It was found that pyridine-containing derivatives of natural chlorins could be obtained in high yields, that they possess chelating properties for platinum, and can be considered as binary agents in cancer therapy after successful preclinical trials.

Flores-Cruz R.D., Espinoza-Guillén A., Reséndiz-Acevedo K., Mendoza-Rodríguez V., López-Casillas F., Jiménez-Sánchez A., Méndez F.J., Ruiz-Azuara L.

A strategy for cancer treatment was implemented, based on chemo-photodynamic therapy, utilizing a novel formulation, low-cost system called Cas-ZnONPs. This system consisted of the incorporation of Casiopeina III-ia (CasIII-ia), a hydrophilic copper coordination compound with well-documented anti-neoplastic activity, on Zinc oxide nanoparticles (ZnONPs) with apoptotic activity and lipophilicity, allowing them to permeate biological barriers. Additionally, ZnONPs exhibited fluorescence, with emission at different wavelengths depending on their agglomeration and enabling real-time tracking biodistribution. Also, ZnONPs served as a sensitizer, generating reactive oxygen species (ROS) in situ. In in vitro studies on HeLa and MDA-MB-231 cell lines, a synergistic effect was observed with the impregnated CasIII-ia on ZnONPs. The anticancer activity had an increase in cellular inhibition, depending on the dose of exposure to UV-vis irradiation. In in vivo studies utilized zebrafish models for xenotransplanting stained MDA-MB-231 cells and testing the effectiveness of Cas-ZnONPs treatment. The treatment successfully eliminated cancer cells, both when combined with Photodynamic Therapy (PDT) and when used alone. However, a significantly higher concentration (50 times) of Cas-ZnONPs was required in the absence of PDT. This demonstrates the potential of Cas-ZnONPs in cancer treatment, especially when combined with PDT.

Kirin N.S., Ostroverkhov P.V., Usachev M.N., Birin K.P., Grin M.A.

Objectives. To synthesize Pt-containing derivatives of natural chlorins as potential agents for the combination therapy in oncology. Platinum compounds are known to occupy an important place as chemotherapeutic agents in the treatment of oncological diseases. However, Pt(II) complexes are highly toxic to the body and are not selectively accumulated in tumor cells. If photodynamic and chemotherapy methods are combined in a single drug, the pigments are responsible for the selectivity of conjugate accumulation in the tumor, while a chemotherapeutic agent based on Pt(II) complexes is responsible for the cytotoxic effect on tumor cells. This will not affect healthy cells and thereby minimize the systemic toxicity of the drug to the body.Methods. Methods for the synthesis of pyridine-containing derivatives of natural chlorins and their metal complexes for use as potential binary agents in oncology were applied. As part of the study, the structures of the compounds obtained were confirmed by mass spectrometry, nuclear magnetic resonance spectroscopy, ultraviolet spectroscopy, and high-resolution chromatography-mass spectrometry. Preparative methods, including thin-layer and column chromatography, centrifugation and recrystallization, were used to isolate and purify the compounds obtained.Results. Platinum(II) complexes of pyridine-containing derivatives of natural chlorins were obtained for application in combination therapy in oncology. The schemes for synthesizing the target photosensitizers were optimized, in order to increase the yields and for subsequent transfer to industrial sites.Conclusions. It was found that pyridine-containing derivatives of natural chlorins could be obtained in high yields, that they possess chelating properties for platinum, and can be considered as binary agents in cancer therapy after successful preclinical trials.

Dhoundiyal S., Srivastava S., Kumar S., Singh G., Ashique S., Pal R., Mishra N., Taghizadeh-Hesary F.

AbstractThis review article explores the dynamic field of radiopharmaceuticals, where innovative developments arise from combining radioisotopes and pharmaceuticals, opening up exciting therapeutic possibilities. The in-depth exploration covers targeted drug delivery, delving into passive targeting through enhanced permeability and retention, as well as active targeting using ligand-receptor strategies. The article also discusses stimulus-responsive release systems, which orchestrate controlled release, enhancing precision and therapeutic effectiveness. A significant focus is placed on the crucial role of radiopharmaceuticals in medical imaging and theranostics, highlighting their contribution to diagnostic accuracy and image-guided curative interventions. The review emphasizes safety considerations and strategies for mitigating side effects, providing valuable insights into addressing challenges and achieving precise drug delivery. Looking ahead, the article discusses nanoparticle formulations as cutting-edge innovations in next-generation radiopharmaceuticals, showcasing their potential applications. Real-world examples are presented through case studies, including the use of radiolabelled antibodies for solid tumors, peptide receptor radionuclide therapy for neuroendocrine tumors, and the intricate management of bone metastases. The concluding perspective envisions the future trajectory of radiopharmaceuticals, anticipating a harmonious integration of precision medicine and artificial intelligence. This vision foresees an era where therapeutic precision aligns seamlessly with scientific advancements, ushering in a new epoch marked by the fusion of therapeutic resonance and visionary progress. Graphical Abstract

Li B., Duan L., Shi J., Han Y., Wei W., Cheng X., Cao Y., Kader A., Ding D., Wu X., Gao Y.

Objectives99mTc-HYNIC-PSMA is a novel technetium-99m-labeled small-molecule inhibitor of prostate-specific membrane antigen (PSMA) for detection of prostate cancer. The present study investigated the diagnostic yield of 99mTc-HYNIC-PSMA Single photon emission computed tomography (SPECT)/CT in 147 patients with biochemically recurrent prostate cancer after radical prostatectomy.Methods147 patients with biochemical relapse after radical prostatectomy were finally eligible for this retrospective analysis. The median prostate-specific antigen (PSA) level was 8.26 ng/mL (range, 0.22-187.40 ng/mL). Of the 147 patients, 72 patients received androgen deprivation therapy (ADT) at least 6 months before the 99mTc-HYNIC-PSMA SPECT/CT. All patients underwent planar whole-body scans and subsequent SPECT/CT of the thoracic and abdominal regions after intravenous injection of 705 ± 70 MBq of 99mTc-HYNIC-PSMA. Images were evaluated for the presence and location of PSMA-positive lesions, in which SUVmax were also measured. Detection rates were stratified according to PSA levels, ADT and Gleason scores. The relationships between SUVmax and clinical characteristics were analyzed using univariate and multivariable linear regression models for patients with positive findings.ResultsOf the 147 patients, 99mTc-HYNIC-PSMA SPECT/CT revealed at least one positive lesion in 118 patients with a high detection rate (80.3%). The detection rates were 48.6% (17/35), 85.1% (40/47), 92.1% (35/38), and 96.3% (26/27) at PSA levels of greater than 0.2 to 2, greater than 2 to 5, greater than 5 to 10, and greater than 10 ng/mL, respectively. PSMA SPECT/CT indicated local recurrence, lymph node metastases, bone metastases, and visceral metastases in 14 (9.5%), 73 (49.7%), 48 (32.7%) and 3 (2.0%) patients. The detection rates of local recurrence and metastasis increased with increasing PSA levels. The detection rate was higher in patients treated with ADT than those without (90.3% vs. 70.7%; P =0.0029). In patients with Gleason scores ≥8, detection rate was slightly higher than those with ≤7 (81.7% vs. 78.5%), but not statistically significant (P = 0.6265). Multivariable linear regression analysis showed a significant correlation of PSA levels and ADT with SUVmax (P=0.0005 and P=0.0397).Conclusions99mTc-HYNIC-PSMA SPECT/CT offers high detection rates for biochemically recurrent prostate cancer after radical prostatectomy. The detection rate and SUVmax were positively correlated with PSA levels and ADT.

Maurin M., Wyczółkowska M., Sawicka A., Sikora A.E., Karczmarczyk U., Janota B., Radzik M., Kłudkiewicz D., Pijarowska-Kruszyna J., Jaroń A., Wojdowska W., Garnuszek P.

Despite significant advances in nuclear medicine for diagnosing and treating prostate cancer (PCa), research into new ligands with increasingly better biological properties is still ongoing. Prostate-specific membrane antigen (PSMA) ligands show great potential as radioisotope carriers for the diagnosis and therapy of patients with metastatic PCa. PSMA is expressed in most types of prostate cancer, and its expression is increased in poorly differentiated, metastatic, and hormone-refractory cancers; therefore, it may be a valuable target for the development of radiopharmaceuticals and radioligands, such as urea PSMA inhibitors, for the precise diagnosis, staging, and treatment of prostate cancer. Four developed PSMA-HYNIC inhibitors for technetium-99m labeling and subsequent diagnosis were subjected to preclinical in vitro and in vivo studies to evaluate and compare their diagnostic properties. Among the studied compounds, the PSMA-T4 (Glu-CO-Lys-L-Trp-4-Amc-HYNIC) inhibitor showed the best biological properties for the diagnosis of PCa metastases. [99mTc]Tc-PSMA-T4 also showed effectiveness in single-photon emission computed tomography (SPECT) studies in humans, and soon, its usefulness will be extensively evaluated in phase 2/3 clinical trials.

Vyalba F.Y., Ivantsova A.V., Zhdanova K.A., Usachev M.N., Gradova M.A., Bragina N.A.

meso -Arylporphyrin containing two external chelating 2,2 ' :6 ' ,2 ' -terpyridine fragments and its zinc complex were synthesized. The key step comprised the amide bond formation between the porphyrin diamine derivative and 4 ' -(4-carboxyphenyl)-2,2 ' :6 ' ,2 ' -terpyridine. The compounds obtained seem to be potent for photodynamic therapy and diagnosis.

Grin M., Suvorov N., Ostroverkhov P., Pogorilyy V., Kirin N., Popov A., Sazonova A., Filonenko E.

When conducting combined therapy of malignant neoplasms, treatment methods with various mechanisms of antitumor effects are used, while an additive or even synergistic effect can be realized. Combination treatment regimens are aimed at increasing the efficiency and, above all, at the complete eradication of the tumor, which can be achieved either by suppressing the survival mechanisms in PDT-resistant tumor cells or by pre-attenuation of tumor cells so that they become more susceptible to subsequent PDT. Photodynamic therapy is an approved medical technology for the treatment of various malignant neoplasms, and several precancerous and non-cancer diseases. To date, numerous data have been published on the combined use of PDT with traditional and innovative methods of treatment. This review considers research in this area in recent years.

Polivanova A.G., Solovieva I.N., Botev D.O., Yuriev D.Y., Mylnikova A.N., Oshchepkov M.S.

Objectives. The chemistry of 67Ga and 68Ga radionuclides plays a key role in nuclear medicine for applications in radiopharmaceuticals, in particular, in noninvasive in vivo molecular imaging techniques. The use of radiometals for labeling biomolecules typically requires the use of bifunctional chelators, which contain a functional group for covalent bonding with the targeting vector in addition to the polydentate fragment coordinating the metal. The aim of the present review article is to analyze the currently accumulated experimental material on the development and application of bifunctional chelators of gallium cations in medical research, as well as to identify the main requirements for the structure of the chelator and its complexes with 68Ga, which are used to create effective Gabased pharmaceutical preparations.Results. The review analyzed macrocyclic bifunctional chelators forming stable in vivo complexes with 68Ga and acyclic chelators, whose main advantage is faster complexation kinetics due to the short half-life of 68Ga. The advantages and disadvantages of both types of ligands were evaluated. In addition, a critical analysis of the binding constants and the conditions for the formation of complexes was presented. Examples of the influence of the geometry, lipophilicity, and total charge of the metal complex on the biodistribution of target radiopharmaceuticals were also given.Conclusions. Despite the progress made in the considered areas of bifunctional chelators, the problem of correlating the chemical structure of a metal-based radiopharmaceutical with its behavior in vivo remains important. Comparative studies of drugs having an identical targeting vector but containing different bifunctional chelating agents could help further elucidate the effectof metal chelate moiety on pharmacokinetics. In order to create effective bifunctional chelating agents, it is necessary to take into account such factors as the stability and inertness of the chelator and its complexes under physiological conditions, lipophilicity, complexation kinetics, chelation selectivity, combinatoriality of the basic structure, along with economic aspects, e.g., the availability of raw materials and the complexity of the synthesis scheme.

Bolzati C., Salvarese N., Spolaore B., Vittadini A., Forrer D., Brunello S., Ghiani S., Maiocchi A.

The incorporation of bioactive molecules into a water-soluble [99mTc][Tc(N)(PNP)]-based mixed compound is described. The method, which exploits the chemical properties of the new [99mTc][Tc(N)(PNP3OH)]2+ synthon [PNP3OH = N,N-bis(di-hydroxymethylenphosphinoethyl)methoxyethylamine], was successfully applied to the labeling of small, medium (cysteine-functionalized biotin and c-RGDfK pentapeptide), and large molecules. Apomyoglobin was chosen as a model protein and derivatized via site-specific enzymatic reaction catalyzed by transglutaminase (TGase) with the H-Cys-Gly-Lys-Gly-OH tetrapeptide for the insertion in the protein sequence of a reactive N-terminal Cys for 99mTc chelation. Radiosyntheses were performed under physiological conditions at room temperature within 30 min. They were reproducible, highly specific, and quantitative. Heteroleptic complexes are hydrophilic and stable. Biodistributions of the selected compounds show favorable pharmacokinetics within 60 min post-injection and predominant elimination through the renal-urinary pathway. In a wider perspective, these data suggest a role of the [99mTc][Tc(N)(PNP)] technology in the labeling of temperature-sensitive biomolecules, especially targeting proteins for SPECT imaging.

Filonenko E.V.

In recent years, the development of methods of photodynamic therapy (PDT) and photodynamic photodiagnostics (PD) in Russia is characterized by an intensive rise, steadily growing interest of specialists from various medical specialties in the method of specialists from various medical specialties, an increase in the level of equipment number of hospitals with the necessary equipment for performing PD and PDT, the and the emergence of new photosensitizers on the pharmaceutical market, and an increasing increase in the level of patients’ confidence in these methods. This study analyzes the dynamics of the development of the clinical application and scientific developments of PD and PDT over the past decade in Russia in terms of the volume of public procurement of photosensitizers, as well as the activity of research work in the field of PD and PDT, the number of candidate and doctoral dissertations theses on this topic and the number of scientific publications in the RSCI. 688 contracts for the supply of photosensitizers for clinical use were analyzed. The analysis showed a stable annual growth in the volume of public procurement of photosensitizers, an increase in the number of subjects of the Russian Federation and clinical centers that purchase photosensitizers through the portal www.zakupki.gov.ru. From 2014 to 2020, the total volume of public procurement of all photosensitizers increased by 8 times (from 36.42 million rubles (3.58 thousand packages) to 307.37 million rubles (18.99 thousand packages)). The annual increase in the volume of public procurement in numerical terms over the previous 6 years ranged from 9.4% to 63.2% in different years. The main share of state purchases of photosensitizers falls on Moscow and St. Petersburg, h. However, in recent years there has been a noticeable trend towards an increase in sales of photosensitizers in the regions. Thus, in recent years, the share of purchases of photosensitizers in the constituent entities of the Russian Federation with a population of less than 1 million people has significantly increased (from 2.9% of the total number of purchases in 2014 to 25.3% in 2020). Also, in recent years, there has been a significant increase in the activity of research work activity in the field of PD and PDT. The number of defended candidate and doctoral dissertations theses defended in the field of PD and PDT photodynamic therapy and fluorescent diagnostics has been steadily high in recent years and, in some scientific specialties, reaches 2-3% of the total number of defended dissertations theses defended in these specialties. The increase in the total number of publications over 10 years according to the RSCI was 224% (from 218 publications in 2014 to 489 publications in 2019), according to the RSCI. The results obtained confirm the growing demand for photosensitizers for photodynamic therapy and fluorescence diagnostics in clinical practice, the expansion of the geography of the use of methods, as well and the stable interest in this topic in the research environment.

Yang Y., Chen F., Xu N., Yao Q., Wang R., Xie X., Zhang F., He Y., Shao D., Dong W., Fan J., Sun W., Peng X.

Although chemo-photodynamic therapy demonstrates promising synergetic therapeutic effects in malignant tumors, the light-controlled drug release, synergism and biocompatibility of current nanocarriers are limited. Herein, we report a red light-responsive, self-destructive carrier constructed using polyethylene glycol-modified, diselenide-bridged mesoporous silica nanoparticles. The carrier is co-encapsulated with the chemo-drug doxorubicin and the photosensitizer methylene blue for chemo-photodynamic therapy. Upon low-dose red light irradiation during photodynamic therapy (PDT), the reactive oxygen species (ROS) mediates a diselenide bond cleavage resulting in the degradation of the organosilica matrix and a dual drug release. This, in turn, results in a synergistic chemo-photodynamic performance in vitro and in vivo. More importantly, such cascade chemo-PDT boosts immunogenic cell death and robust anti-tumor immunity responses. Combination with a PD-1 checkpoint blockade further evokes a series of systemic immunity responses that suppress distant tumor growth and the pulmonary metastasis of breast cancer, as well as offer long-term protection against recurrent tumors. The presented work offers a controllable self-destruction nanoplatform for cascade-amplifying chemo-photodynamic therapy in response to external red light radiation.

Otvagin V.F., Kuzmina N.S., Kudriashova E.S., Nyuchev A.V., Gavryushin A.E., Fedorov A.Y.

Photodynamic therapy (PDT) is a treatment modality where light-mediated activation of photosensitizers in a patient's body leads to the generation of cytotoxic reactive oxygen species (ROS), eliminating cancer cells. One direction that has been firmly established over past years is the conjugation of photosensitizers with various molecules that demonstrate their own cytotoxic activity. As a result, improved selectivity and treatment outcomes are observed compared to those of unconjugated drugs. The attractiveness of such an approach is due to the variability of cytotoxic warheads and specific linkers available for the construction of conjugates. In this review, we summarize and analyze data concerning these inventions with the ultimate goal to find a promising conjugation partner for a porphyrinoid-based photosensitizer. The current challenges toward successful conjugation are also outlined and discussed. We hope that this review will motivate researchers to pay closer attention to conjugates and possibilities hidden in these molecules for the PDT of cancer.

Hao Y., Chung C.K., Yu Z., Huis in ‘t Veld R.V., Ossendorp F.A., ten Dijke P., Cruz L.J.

Photodynamic therapy (PDT), in which a light source is used in combination with a photosensitizer to induce local cell death, has shown great promise in therapeutically targeting primary tumors with negligible toxicity and minimal invasiveness. However, numerous studies have shown that noninvasive PDT alone is not sufficient to completely ablate tumors in deep tissues, due to its inherent shortcomings. Therefore, depending on the characteristics and type of tumor, PDT can be combined with surgery, radiotherapy, immunomodulators, chemotherapy, and/or targeted therapy, preferably in a patient-tailored manner. Nanoparticles are attractive delivery vehicles that can overcome the shortcomings of traditional photosensitizers, as well as enable the codelivery of multiple therapeutic drugs in a spatiotemporally controlled manner. Nanotechnology-based combination strategies have provided inspiration to improve the anticancer effects of PDT. Here, we briefly introduce the mechanism of PDT and summarize the photosensitizers that have been tested preclinically for various cancer types and clinically approved for cancer treatment. Moreover, we discuss the current challenges facing the combination of PDT and multiple cancer treatment options, and we highlight the opportunities of nanoparticle-based PDT in cancer therapies.

Yu H., Li Y., Zhang Z., Ren J., Zhang L., Xu Z., Kang Y., Xue P.

Disturbance in redox homeostasis always leads to oxidative damages to cellular components, which inhibits cancer cell proliferation and causes tumor regression. Therefore, synergistic effects arising from cellular redox imbalance together with other treatment modalities are worth further investigation. Herein, a metal-organic framework nanosystem (NMOF) based on coordination between Fe (III) and 4,4,4,4-(porphine-5,10,15,20-tetrayl) tetrakis (benzoic acid) (TCPP) was synthesized through a one-pot method. After surface capping of silk fibroin (SF) to form NMOF@SF nanoparticles (NPs), this nanoplatform can serve as an eligible nanocarrier to deliver tirapazamine (TPZ), a hypoxia-activated precursor. As-developed NS@TPZ (NST) NPs remained inactive in the normal tissue, whereas became highly active upon endocytosis by tumor cells via glutathione (GSH)-mediated reduction of Fe (III) into Fe (II), further enabling Fe (II)-mediated chemodynamic therapy (CDT). Upon optical laser irradiation, TCPP-mediated photodynamic therapy (PDT) coordinated with CDT to aggravate intracellular oxidative stress. Thus, such reactive oxygen species accumulation and GSH deprivation contributed to a deleterious redox dyshomeostasis. On the other hand, local deoxygenation caused by PDT can increase the cytotoxicity of released TPZ, which significantly improved the integral therapeutic effectiveness relying on the combined redox balance disruption and bioreductive chemotherapy. More importantly, severe immunogenic cell death can be triggered by the combinatorial treatment modalities and the presence of SF, which facilitated an almost complete tumor eradication in vivo. Taken together, this paradigm provides an insightful strategy for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy, which can remarkably enhance antitumor efficacy with negligible adverse effects. STATEMENT OF SIGNIFICANCE: Recently, silk fibroin (SF) has been demonstrated to be effective in activating antitumor immune system through polarization tumor-associated macrophages into M1 subtype. However, engineering SF into multifunctional nanocomposites is seldom reported for combination tumor therapy. In another aspect, disruption of redox homeostasis becomes increasingly attractive for tumor suppression with high clinical-relevance. Herein, we established a newfashioned NMOF nanosystem, named as NST, for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy. This platform takes advantages of Fe2+/Fe3+ coupled Fenton-like reaction and GSH depletion, as well as TCPP-mediated photosensitization for admirable redox unbalancing, which further initiates hypoxia-relevant toxin of TPZ for chemotherapy. Finally, combinatorial treatments and the presence of SF could trigger ICD for rendering a complete tumor eradication in vivo.

Tikhonov S., Ostroverkhov P., Suvorov N., Mironov A., Efimova Y., Plutinskaya A., Pankratov A., Ignatova A., Feofanov A., Diachkova E., Vasil’ev Y., Grin M.

Photodynamic therapy (PDT) is currently one of the most promising methods of cancer treatment. However, this method has some limitations, including a small depth of penetration into biological tissues, the low selectivity of accumulation, and hypoxia of the tumor tissues. These disadvantages can be overcome by combining PDT with other methods of treatment, such as radiation therapy, neutron capture therapy, chemotherapy, etc. In this work, potential drugs were obtained for the first time, the molecules of which contain both photodynamic and chemotherapeutic pharmacophores. A derivative of natural bacteriochlorophyll a with a tin IV complex, which has chemotherapeutic activity, acts as an agent for PDT. This work presents an original method for obtaining agents of combined action, the structure of which is confirmed by various physicochemical methods of analysis. The method of molecular modeling was used to investigate the binding of the proposed drugs to DNA. In vitro biological tests were carried out on several lines of tumor cells: Hela, A549, S37, MCF7, and PC-3. It was shown that the proposed conjugates of binary action for some cell lines had a dark cytotoxicity that was significantly higher (8–10 times) than the corresponding metal complexes of amino acids, which was explained by the targeted chemotherapeutic action of the tin (IV) complex due to chlorin. The greatest increase in efficiency relative to the initial dipropoxy-BPI was found for the conjugate with lysine as a chelator of the tin cation relative to cell lines, with the following results: S-37 increased 3-fold, MCF-7 3-fold, and Hela 2.4-fold. The intracellular distribution of the obtained agents was also studied by confocal microscopy and showed a diffuse granular distribution with predominant accumulation in the near nuclear region.

Tojo T., Niiuchi A., Kondo T., Yuasa M.

Porphyrin selectively shows tumour accumulation and has attracted attention as a carrier molecule for drug delivery systems (DDS). Porphyrin has two functional sites termed the meso- and β-positions. In previous work, meso-porphyrin derivatives with an alkyl group were found to exhibit greater accumulation in human breast cancer cells (MCF-7). To identify the correlation between porphyrin accumulation and functional porphyrin positions of other functional groups, the accumulation of porphyrin derivatives with a phenyl group was investigated. The β-porphyrin derivative with a phenyl group showed higher accumulation in MCF-7 cells and greater affinity for albumin than the meso-porphyrin derivative. The results of density functional theory (DFT) calculations suggest that the β-porphyrin derivative with a phenyl group had higher planarity across the total structure than the meso-porphyrin derivative. It was concluded that the greater planarity of the β-porphyrin derivative with a phenyl group might lead to superior MCF-7 cell accumulation.