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Pharmaceutics
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Kinase Inhibitors: Innovative Delivery Strategies and Anticancer Potential
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Kinase Inhibitors: Innovative Delivery Strategies and Anticancer Potential

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: 30 September 2025 | Viewed by 2408

Special Issue Editors

Dr. Federica Poggialini

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Guest Editor
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via A. Moro 2, 53100 Siena, Italy
Interests: oral drug delivery; ADME/DMPK; anticancer agents; pyrazolo[3,4-d]pyrimidines; analytical; kinase inhibitors
Dr. Elena Dreassi

E-Mail Website
Guest Editor
Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, 53100 Siena, Italy
Interests: anticancer agents; targeted delivery; analytics; medicinal chemistry; ADME/DMPK
Special Issues, Collections and Topics in MDPI journals
Dr. Chiara Vagaggini

E-Mail Website
Guest Editor
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via A. Moro 2, 53100 Siena, Italy
Interests: anticancer nanoformulations; oral drug delivery; drug discovery; gut microbiota; ADME/DMPK; analytical chemistry; validation of chromatographic methods

Special Issue Information

Dear Colleagues,

Cancer remains a major global health issue, with huge efforts being made to develop more effective and targeted treatments. The dynamic landscape of cancer research has undergone a remarkable transformation with the advent of targeted therapies, most notably the development of kinase inhibitors. In this context, the discovery and development of anticancer drugs, such as kinase inhibitors, has been marked as a turning point in the treatment of different types of tumors. Indeed, these enzymes, responsible for catalysing phosphorylation reactions, are central to various cellular processes such as cell division, cell death, transcription and metabolism. Their dysregulation has been implicated in a wide range of diseases, including many forms of cancer. The success of imatinib, the first oral tyrosine kinase inhibitor approved by the Federal Drug Administration (FDA) in 2001 for chronic myelogenous leukemia, has paved the way for the extensive use of kinase inhibitors (KIs) as anticancer agents.

Recent advances in drug delivery systems have significantly enhanced the efficacy and specificity of kinase inhibitors. Innovative delivery platforms, such as nanoparticles, liposomes, dendrimers and polymeric micelles, are being utilized to improve the targeted delivery of kinase inhibitors to tumor sites. These technologies aim to increase drug accumulation in cancerous tissues, reduce systemic toxicity and overcome mechanisms of drug resistance. Additionally, stimuli-responsive delivery systems that release drugs in response to specific tumor microenvironment conditions, such as pH, temperature or enzymatic activity, are being explored to further refine the precision of these treatments.

This Special Issue of Pharmaceutics welcomes original research papers and high-impact reviews focused on the development of new kinase inhibitors, as well as drug delivery and formulation studies, biological and ADME/DMPK evaluation. We encourage contributions that highlight novel drug delivery strategies and their role in enhancing the therapeutic potential of kinase inhibitors in cancer treatment.

Dr. Federica Poggialini
Dr. Elena Dreassi
Dr. Chiara Vagaggini
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • kinase inhibitors
  • ADME
  • DMPK
  • formulation studies
  • anticancer activity
  • drug discovery
  • targeted therapy
  • drug delivery
  • innovative delivery platforms

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Published Papers (3 papers)

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Research

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15 pages, 1872 KiB  
Article
Evaluation of Antitumoral Activity in a 3D Cell Model of a Src Inhibitor Prodrug for Glioblastoma Treatment
by Letizia Clementi, Federica Poggialini, Francesca Musumeci, Julia Taglienti, Emanuele Cornacchia, Chiara Vagaggini, Anna Carbone, Giancarlo Grossi, Elena Dreassi, Adriano Angelucci and Silvia Schenone
Pharmaceutics 2025, 17(6), 704; https://doi.org/10.3390/pharmaceutics17060704 - 27 May 2025
Viewed by 420
Abstract
Background: Three-dimensional (3D) cell models may bridge the gap between two-dimensional (2D) cell cultures and animal models. Technical advances have led to the development of 3D-bioprinted cell models, characterized by greater reproducibility and the ability to mimic in vivo conditions. Glioblastoma multiforme [...] Read more.
Background: Three-dimensional (3D) cell models may bridge the gap between two-dimensional (2D) cell cultures and animal models. Technical advances have led to the development of 3D-bioprinted cell models, characterized by greater reproducibility and the ability to mimic in vivo conditions. Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with poor clinical outcomes due to its heterogeneity, angiogenic activity, and invasiveness. Src family kinases (SFKs) play a crucial role in GBM progression, making them attractive targets for drug development. Here, we show results about the pharmacological profile of a new prodrug synthesized from a Src inhibitor, SI306. Methods: Three-dimensional-bioprinted GBM cell models were used in predicting the antitumor activity of the prodrug SI306-PD2 with respect to its precursor, SI306. Results: Since the prodrug releases the active inhibitor through the cleavage by specific enzymes, SI306-PD2 was analyzed for stability and release kinetics in various media, including fetal bovine serum (FBS), which is normally used in cell culture. In comparison to SI306, SI306-PD2 demonstrated higher solubility in water, higher permeability across gastrointestinal and blood–brain barrier membranes, and the ability to release the drug in the presence of FBS progressively. In the 2D GBM cell model, using U87 and U251 cell lines, both compounds similarly reduced tumor cell viability. In 3D-bioprinted cell models, in the presence of an FBS-free medium, SI306-PD2 exhibited a more effective antitumor activity compared to SI306, reducing the proliferation and diameter of U251 spheroids grown within the bioprinted scaffold in a statistically significant manner. The analysis of proteins extracted from 3D scaffolds confirmed that SI306-PD2 inhibited Src activation more efficiently than SI306. Conclusions: Our study suggests that, when tissue permeability represents a discriminating characteristic, bioprinted cell models can provide a valid alternative for studying the cytotoxicity of new antitumor compounds. This approach has permitted us to ascertain the potential of the prodrug SI306-PD2 as a therapeutic agent for GBM, demonstrating better tissue penetration and antiproliferative efficacy compared to the precursor compound SI306. Full article
(This article belongs to the Special Issue Kinase Inhibitors: Innovative Delivery Strategies and Anticancer Potential)
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19 pages, 1992 KiB  
Article
Pharmacokinetic Interaction Between Olaparib and Regorafenib in an Animal Model
by Danuta Szkutnik-Fiedler, Agnieszka Karbownik, Filip Otto, Julia Maciejewska, Alicja Kuźnik, Tomasz Grabowski, Anna Wolc, Edmund Grześkowiak, Joanna Stanisławiak-Rudowicz and Edyta Szałek
Pharmaceutics 2024, 16(12), 1575; https://doi.org/10.3390/pharmaceutics16121575 - 9 Dec 2024
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Abstract
Background: Olaparib (OLA) and regorafenib (REG) are metabolized by the CYP3A4 isoenzyme of cytochrome P450. Both drugs are also substrates and inhibitors of the membrane transporters P-glycoprotein and BCRP. Therefore, the potential concomitant use of OLA and REG may result in clinically relevant [...] Read more.
Background: Olaparib (OLA) and regorafenib (REG) are metabolized by the CYP3A4 isoenzyme of cytochrome P450. Both drugs are also substrates and inhibitors of the membrane transporters P-glycoprotein and BCRP. Therefore, the potential concomitant use of OLA and REG may result in clinically relevant drug–drug interactions. Knowledge of the influence of membrane transporters and cytochrome P450 enzymes on the pharmacokinetics of drugs makes it possible to assess their impact on the efficacy and safety of therapy. Purpose: The study aimed to evaluate the bilateral pharmacokinetic interactions of OLA and REG and its active metabolites after a single administration in healthy rats. Methods: The study was performed in male Wistar rats (n = 24) randomly divided into three groups: one study group, IREG+OLA (n = 8), received REG with OLA, and two control groups, IIREG (n = 8) and IIIOLA (n = 8), received REG and OLA, respectively. The concentrations of OLA, REG, REG-N-oxide (M-2), and N-desmethyl-REG-N-oxide (M-5) were determined by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). The values of the pharmacokinetic parameters of OLA, REG, M-2, and M-5 were determined by non-compartmental analysis with linear interpolation. Results: After OLA administration, the pharmacokinetic parameters of REG (AUC0–∞, tmax, and t0.5) increased significantly by 3.38-, 2.66-, and 1.82-fold, respectively. On the other hand, REG elimination parameters, i.e., kel and Cl/F, were significantly reduced in the study group by 1.77- and 1.70-fold, respectively. In the study group, Cmax and AUC0–t values were also 7.22- and 8.86-fold higher for M-2 and 16.32- and 17.83-fold higher for M-5, respectively. The Metabolite M-2/Parent and Metabolite M-5/Parent ratios for Cmax and AUC0–t increased by 6.52-, 10.74-, 28-, and 13-fold, respectively. After administration of OLA with REG, the Cmax, AUC0–t, and AUC0–∞ of OLA increased by 2.0-, 3.4-, and 3.4-fold, respectively, compared to the control group. Meanwhile, Cl/F and Vd/F of OLA were significantly decreased in the presence of REG. Conclusions: OLA was shown to significantly affect the pharmacokinetics of REG and its active metabolites M-2 and M-5 in rats after co-administration of both drugs. There was also a significant effect of REG on the pharmacokinetics of OLA, which may have clinical relevance. The AUC ratios (study group/control group) were 3.41 and 3.39 for REG and OLA, respectively, indicating that REG and OLA were moderate inhibitors in this preclinical study. The results obtained need to be confirmed in clinical studies. This study may provide guidance on the safety of using both drugs in clinical practice. Full article
(This article belongs to the Special Issue Kinase Inhibitors: Innovative Delivery Strategies and Anticancer Potential)
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Review

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42 pages, 2266 KiB  
Review
Innovative Approaches in Cancer Treatment: Emphasizing the Role of Nanomaterials in Tyrosine Kinase Inhibition
by Antónia Kurillová, Libor Kvítek and Aleš Panáček
Pharmaceutics 2025, 17(6), 783; https://doi.org/10.3390/pharmaceutics17060783 - 16 Jun 2025
Viewed by 261
Abstract
Medical research is at the forefront of addressing pressing global challenges, including preventing and treating cardiovascular, autoimmune, and oncological diseases, neurodegenerative disorders, and the growing resistance of pathogens to antibiotics. Understanding the molecular mechanisms underlying these diseases, using advanced medical approaches and cutting-edge [...] Read more.
Medical research is at the forefront of addressing pressing global challenges, including preventing and treating cardiovascular, autoimmune, and oncological diseases, neurodegenerative disorders, and the growing resistance of pathogens to antibiotics. Understanding the molecular mechanisms underlying these diseases, using advanced medical approaches and cutting-edge technologies, structure-based drug design, and personalized medicine, is critical for developing effective therapies, specifically anticancer treatments. Background/Objectives: One of the key drivers of cancer at the cellular level is the abnormal activity of protein enzymes, specifically serine, threonine, or tyrosine residues, through a process known as phosphorylation. While tyrosine kinase-mediated phosphorylation constitutes a minor fraction of total cellular phosphorylation, its dysregulation is critically linked to carcinogenesis and tumor progression. Methods: Small-molecule inhibitors, such as imatinib or erlotinib, are designed to halt this process, restoring cellular equilibrium and offering targeted therapeutic approaches. However, challenges persist, including frequent drug resistance and severe side effects associated with these therapies. Nanomedicine offers a transformative potential to overcome these limitations. Results: By leveraging the unique properties of nanomaterials, it is possible to achieve precise drug delivery, enhance accumulation at target sites, and improve therapeutic efficacy. Examples include nanoparticle-based delivery systems for TKIs and the combination of nanomaterials with photothermal or photodynamic therapies to enhance treatment effectiveness. Combining nanomedicine with traditional treatments holds promise and perspective for synergistic and more effective cancer management. Conclusions: This review delves into recent advances in understanding tyrosine kinase activity, the mechanisms of their inhibition, and the innovative integration of nanomedicine to revolutionize cancer treatment strategies. Full article
(This article belongs to the Special Issue Kinase Inhibitors: Innovative Delivery Strategies and Anticancer Potential)
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