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14 pages, 3308 KiB

Open AccessArticle

Optimization of a Modular Nanotransporter Design for Targeted Intracellular Delivery of Photosensitizer

by Rena T. Alieva, Alexey V. Ulasov, Yuri V. Khramtsov, Tatiana A. Slastnikova, Tatiana N. Lupanova, Maria A. Gribova, Georgii P. Georgiev and Andrey A. Rosenkranz

Pharmaceutics 2024, 16(8), 1083; https://doi.org/10.3390/pharmaceutics16081083 - 18 Aug 2024

Viewed by 1312

Abstract

Modular nanotransporters (MNTs) are drug delivery systems for targeted cancer treatment. As MNTs are composed of several modules, they offer the advantage of high specificity and biocompatibility in delivering drugs to the target compartment of cancer cells. The large carrier module brings together [...] Read more.

Modular nanotransporters (MNTs) are drug delivery systems for targeted cancer treatment. As MNTs are composed of several modules, they offer the advantage of high specificity and biocompatibility in delivering drugs to the target compartment of cancer cells. The large carrier module brings together functioning MNT modules and serves as a platform for drug attachment. The development of smaller-sized MNTs via truncation of the carrier module appears advantageous in facilitating tissue penetration. In this study, two new MNTs with a truncated carrier module containing either an N-terminal (MNT_N) or a C-terminal (MNT_C) part were developed by genetic engineering. Both new MNTs demonstrated a high affinity for target receptors, as revealed by fluorescent-labeled ligand-competitive binding. The liposome leakage assay proved the endosomolytic activity of MNTs. Binding to the importin heterodimer of each truncated MNT was revealed by a thermophoresis assay, while only MNT_N possessed binding to Keap1. Finally, the photodynamic efficacy of the photosensitizer attached to MNT_N was significantly higher than when attached to either MNT_C or the original MNTs. Thus, this work reveals that MNT’s carrier module can be truncated without losing MNT functionality, favoring the N-terminal part of the carrier module due to its ability to bind Keap1. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Targeted Delivery of Anticancer Agents Engaging Cell Specific Mechanisms)

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17 pages, 2945 KiB

Open AccessArticle

Modular Nanotransporters Delivering Biologically Active Molecules to the Surface of Mitochondria

by Yuri V. Khramtsov, Alexey V. Ulasov, Tatiana A. Slastnikova, Andrey A. Rosenkranz, Tatiana N. Lupanova, Georgii P. Georgiev and Alexander S. Sobolev

Pharmaceutics 2023, 15(12), 2687; https://doi.org/10.3390/pharmaceutics15122687 - 27 Nov 2023

Cited by 4 | Viewed by 1948

Abstract

Treatment of various diseases, in particular cancer, usually requires the targeting of biologically active molecules at a selected subcellular compartment. We modified our previously developed modular nanotransporters (MNTs) for targeting mitochondria. The new MNTs are capable of binding to the protein predominantly localized [...] Read more.

Treatment of various diseases, in particular cancer, usually requires the targeting of biologically active molecules at a selected subcellular compartment. We modified our previously developed modular nanotransporters (MNTs) for targeting mitochondria. The new MNTs are capable of binding to the protein predominantly localized on the outer mitochondrial membrane, Keap1. These MNTs possessing antiKeap1 monobody co-localize with mitochondria upon addition to the cells. They efficiently interact with Keap1 both in solution and within living cells. A conjugate of the MNT with a photosensitizer, chlorin e₆, demonstrated significantly higher photocytotoxicity than chlorin e₆ alone. We assume that MNTs of this kind can improve efficiency of therapeutic photosensitizers and radionuclides emitting short-range particles. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Targeted Delivery of Anticancer Agents Engaging Cell Specific Mechanisms)

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15 pages, 2788 KiB

Open AccessArticle

Nucleoside Analog 2′,3′-Isopropylidene-5-Iodouridine as Novel Efficient Inhibitor of HIV-1

by Ksenia Glumakova, Georgy Ivanov, Valeria Vedernikova, Lena Shyrokova, Timofey Lebedev, Andrei Stomakhin, Anastasia Zenchenko, Vladimir Oslovsky, Mikhail Drenichev, Vladimir Prassolov and Pavel Spirin

Pharmaceutics 2023, 15(10), 2389; https://doi.org/10.3390/pharmaceutics15102389 - 27 Sep 2023

Viewed by 1611

Abstract

Nucleoside reverse transcriptase inhibitors are the first class of drugs to be approved by the FDA for the suppression of HIV-1 and are widely used for this purpose in combination with drugs of other classes. Despite the progress in HIV-1 treatment, there is [...] Read more.

Nucleoside reverse transcriptase inhibitors are the first class of drugs to be approved by the FDA for the suppression of HIV-1 and are widely used for this purpose in combination with drugs of other classes. Despite the progress in HIV-1 treatment, there is still the need to develop novel efficient antivirals. Here the efficiency of HIV-1 inhibition by a set of original 5-substituted uridine nucleosides was studied. We used the replication deficient human immunodeficiency virus (HIV-1)-based lentiviral particles and identified that among the studied compounds, 2′,3′-isopropylidene-5-iodouridine was shown to cause anti-HIV-1 activity. Importantly, no toxic action of this compound against the cells of T-cell origin was found. We determined that this compound is significantly more efficient at suppressing HIV-1 compared to Azidothymidine (AZT) when taken at the high non-toxic concentrations. We did not find any profit when using AZT in combination with 2′,3′-isopropylidene-5-iodouridine. 2′,3′-Isopropylidene-5-iodouridine acts synergistically to repress HIV-1 when combined with the CDK4/6 inhibitor Palbociclib in low non-toxic concentration. No synergistic antiviral action was detected when AZT was combined with Palbociclib. We suggest 2′,3′-isopropylidene-5-iodouridine as a novel perspective non-toxic compound that may be used for HIV-l suppression. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Targeted Delivery of Anticancer Agents Engaging Cell Specific Mechanisms)

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26 pages, 3610 KiB

Open AccessArticle

Influence of the Composition of Cationic Liposomes on the Performance of Cargo Immunostimulatory RNA

by Ali Bishani, Darya M. Makarova, Elena V. Shmendel, Mikhail A. Maslov, Aleksandra V. Sen‘kova, Innokenty A. Savin, Daniil V. Gladkikh, Marina A. Zenkova and Elena L. Chernolovskaya

Pharmaceutics 2023, 15(9), 2184; https://doi.org/10.3390/pharmaceutics15092184 - 23 Aug 2023

Cited by 9 | Viewed by 2392

Abstract

In this study, the impact of different delivery systems on the cytokine-inducing, antiproliferative, and antitumor activities of short immunostimulatory double-stranded RNA (isRNA) was investigated. The delivery systems, consisting of the polycationic amphiphile 1,26-bis(cholest-5-en-3-yloxycarbonylamino)-7,11,16,20 tetraazahexacosan tetrahydrochloride (2X3), and the lipid-helper dioleoylphosphatidylethanolamine (DOPE), were equipped [...] Read more.

In this study, the impact of different delivery systems on the cytokine-inducing, antiproliferative, and antitumor activities of short immunostimulatory double-stranded RNA (isRNA) was investigated. The delivery systems, consisting of the polycationic amphiphile 1,26-bis(cholest-5-en-3-yloxycarbonylamino)-7,11,16,20 tetraazahexacosan tetrahydrochloride (2X3), and the lipid-helper dioleoylphosphatidylethanolamine (DOPE), were equipped with polyethylene glycol lipoconjugates differing in molecular weight and structure. The main findings of this work are as follows: (i) significant activation of MCP-1 and INF-α, β, and γ production in CBA mice occurs under the action of isRNA complexes with liposomes containing lipoconjugates with long PEG chains, while activation of MCP-1 and INF-γ, but not INF-α or β, was observed under the action of isRNA lipoplexes containing lipoconjugates with short PEG chains; (ii) a pronounced antiproliferative effect on B16 melanoma cells in vitro, as well as an antitumor and hepatoprotective effect in vivo, was induced by isRNA pre-complexes with non-pegylated liposomes, while complexes containing lipoconjugates with long-chain liposomes were inactive; (iii) the antitumor activity of isRNA correlated with the efficiency of its accumulation in the cells and did not explicitly depend on the activation of cytokine and interferon production. Thus, the structure of the delivery system plays a vital role in determining the response to isRNA and allows for the choice of a delivery system depending on the desired effect. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Targeted Delivery of Anticancer Agents Engaging Cell Specific Mechanisms)

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Review

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21 pages, 2056 KiB

Open AccessReview

Targeting Mitochondria for Cancer Treatment

by Ljubava D. Zorova, Polina A. Abramicheva, Nadezda V. Andrianova, Valentina A. Babenko, Savva D. Zorov, Irina B. Pevzner, Vasily A. Popkov, Dmitry S. Semenovich, Elmira I. Yakupova, Denis N. Silachev, Egor Y. Plotnikov, Gennady T. Sukhikh and Dmitry B. Zorov

Pharmaceutics 2024, 16(4), 444; https://doi.org/10.3390/pharmaceutics16040444 - 23 Mar 2024

Cited by 6 | Viewed by 2841

Abstract

There is an increasing accumulation of data on the exceptional importance of mitochondria in the occurrence and treatment of cancer, and in all lines of evidence for such participation, there are both energetic and non-bioenergetic functional features of mitochondria. This analytical review examines [...] Read more.

There is an increasing accumulation of data on the exceptional importance of mitochondria in the occurrence and treatment of cancer, and in all lines of evidence for such participation, there are both energetic and non-bioenergetic functional features of mitochondria. This analytical review examines three specific features of adaptive mitochondrial changes in several malignant tumors. The first feature is characteristic of solid tumors, whose cells are forced to rebuild their energetics due to the absence of oxygen, namely, to activate the fumarate reductase pathway instead of the traditional succinate oxidase pathway that exists in aerobic conditions. For such a restructuring, the presence of a low-potential quinone is necessary, which cannot ensure the conventional conversion of succinate into fumarate but rather enables the reverse reaction, that is, the conversion of fumarate into succinate. In this scenario, complex I becomes the only generator of energy in mitochondria. The second feature is the increased proliferation in aggressive tumors of the so-called mitochondrial (peripheral) benzodiazepine receptor, also called translocator protein (TSPO) residing in the outer mitochondrial membrane, the function of which in oncogenic transformation stays mysterious. The third feature of tumor cells is the enhanced retention of certain molecules, in particular mitochondrially directed cations similar to rhodamine 123, which allows for the selective accumulation of anticancer drugs in mitochondria. These three features of mitochondria can be targets for the development of an anti-cancer strategy. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Targeted Delivery of Anticancer Agents Engaging Cell Specific Mechanisms)

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39 pages, 773 KiB

Open AccessReview

Targeted Glioma Therapy—Clinical Trials and Future Directions

by Aleksandr Shikalov, Igor Koman and Natalya M. Kogan

Pharmaceutics 2024, 16(1), 100; https://doi.org/10.3390/pharmaceutics16010100 - 11 Jan 2024

Cited by 11 | Viewed by 5020

Abstract

Glioblastoma multiforme (GBM) is the most common type of glioma, with a median survival of 14.6 months post-diagnosis. Understanding the molecular profile of such tumors allowed the development of specific targeted therapies toward GBM, with a major role attributed to tyrosine kinase receptor [...] Read more.

Glioblastoma multiforme (GBM) is the most common type of glioma, with a median survival of 14.6 months post-diagnosis. Understanding the molecular profile of such tumors allowed the development of specific targeted therapies toward GBM, with a major role attributed to tyrosine kinase receptor inhibitors and immune checkpoint inhibitors. Targeted therapeutics are drugs that work by specific binding to GBM-specific or overexpressed markers on the tumor cellular surface and therefore contain a recognition moiety linked to a cytotoxic agent, which produces an antiproliferative effect. In this review, we have summarized the available information on the targeted therapeutics used in clinical trials of GBM and summarized current obstacles and advances in targeted therapy concerning specific targets present in GBM tumor cells, outlined efficacy endpoints for major classes of investigational drugs, and discussed promising strategies towards an increase in drug efficacy in GBM. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Targeted Delivery of Anticancer Agents Engaging Cell Specific Mechanisms)

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21 pages, 2549 KiB

Open AccessEditor’s ChoiceReview

DNA Repair Inhibitors: Potential Targets and Partners for Targeted Radionuclide Therapy

by Honoka Obata, Mikako Ogawa and Michael R. Zalutsky

Pharmaceutics 2023, 15(7), 1926; https://doi.org/10.3390/pharmaceutics15071926 - 11 Jul 2023

Cited by 9 | Viewed by 3359

Abstract

The present review aims to explore the potential targets/partners for future targeted radionuclide therapy (TRT) strategies, wherein cancer cells often are not killed effectively, despite receiving a high average tumor radiation dose. Here, we shall discuss the key factors in the cancer genome, [...] Read more.

The present review aims to explore the potential targets/partners for future targeted radionuclide therapy (TRT) strategies, wherein cancer cells often are not killed effectively, despite receiving a high average tumor radiation dose. Here, we shall discuss the key factors in the cancer genome, especially those related to DNA damage response/repair and maintenance systems for escaping cell death in cancer cells. To overcome the current limitations of TRT effectiveness due to radiation/drug-tolerant cells and tumor heterogeneity, and to make TRT more effective, we propose that a promising strategy would be to target the DNA maintenance factors that are crucial for cancer survival. Considering their cancer-specific DNA damage response/repair ability and dysregulated transcription/epigenetic system, key factors such as PARP, ATM/ATR, amplified/overexpressed transcription factors, and DNA methyltransferases have the potential to be molecular targets for Auger electron therapy; moreover, their inhibition by non-radioactive molecules could be a partnering component for enhancing the therapeutic response of TRT. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Targeted Delivery of Anticancer Agents Engaging Cell Specific Mechanisms)

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32 pages, 4208 KiB

Open AccessReview

Prospects of Using Protein Engineering for Selective Drug Delivery into a Specific Compartment of Target Cells

by Andrey A. Rosenkranz and Tatiana A. Slastnikova

Pharmaceutics 2023, 15(3), 987; https://doi.org/10.3390/pharmaceutics15030987 - 19 Mar 2023

Cited by 6 | Viewed by 3206

Abstract

A large number of proteins are successfully used to treat various diseases. These include natural polypeptide hormones, their synthetic analogues, antibodies, antibody mimetics, enzymes, and other drugs based on them. Many of them are demanded in clinical settings and commercially successful, mainly for [...] Read more.

A large number of proteins are successfully used to treat various diseases. These include natural polypeptide hormones, their synthetic analogues, antibodies, antibody mimetics, enzymes, and other drugs based on them. Many of them are demanded in clinical settings and commercially successful, mainly for cancer treatment. The targets for most of the aforementioned drugs are located at the cell surface. Meanwhile, the vast majority of therapeutic targets, which are usually regulatory macromolecules, are located inside the cell. Traditional low molecular weight drugs freely penetrate all cells, causing side effects in non-target cells. In addition, it is often difficult to elaborate a small molecule that can specifically affect protein interactions. Modern technologies make it possible to obtain proteins capable of interacting with almost any target. However, proteins, like other macromolecules, cannot, as a rule, freely penetrate into the desired cellular compartment. Recent studies allow us to design multifunctional proteins that solve these problems. This review considers the scope of application of such artificial constructs for the targeted delivery of both protein-based and traditional low molecular weight drugs, the obstacles met on the way of their transport to the specified intracellular compartment of the target cells after their systemic bloodstream administration, and the means to overcome those difficulties. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Targeted Delivery of Anticancer Agents Engaging Cell Specific Mechanisms)

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