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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 15132

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Special Issue Editors

Dr. Mojtaba Falahati

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Guest Editor

Laboratory Experimental Oncology, Department of Pathology, Erasmus MC, 3015GD Rotterdam, The Netherlands
Interests: nanomedicine; drug delivery; protein aggregation

Dr. Timo L. M. Ten-Hagen

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Guest Editor

Laboratory Experimental Oncology, Department of Pathology, Erasmus MC, 3015GD Rotterdam, The Netherlands
Interests: nanomedicine; drug delivery; tumor pathophysiology

Special Issue Information

Dear Colleagues,

In the last decades, interest in the application of drug delivery systems as a potential way to fight cancer has grown rapidly. Targeted drug delivery systems are able to overcome the drawbacks related to conventional drugs, improving their controlled release and treatment efficiency, and allowing multi-drug resistance reversal. Different kinds of nanomaterials-based drug delivery systems have shown promising outcomes against several types of cancers.

The multi-disciplinary topics of interest for this Special Issue include but are not limited to the application of nanotechnology in drug delivery, development of different nanocarriers in bioresponsive drug delivery systems for programmed and on-demand drug release, and the translational applications of nano-based drug delivery systems to pre-clinical and clinical trials for cancer therapy. We welcome both research and review articles.

Dr. Mojtaba Falahati
Dr. Timo L. M. Ten-Hagen
Guest Editors

Manuscript Submission Information

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Keywords

drug delivery
nanoparticles
cancer therapy
targeting strategies
cellular and molecular levels
controlled drug delivery

Published Papers (6 papers)

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Research

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18 pages, 5852 KiB

Open AccessArticle

How Does the Study MD of pH-Dependent Exposure of Nanoparticles Affect Cellular Uptake of Anticancer Drugs?

by Selvaraj Sengottiyan, Alicja Mikolajczyk and Tomasz Puzyn

Int. J. Mol. Sci. 2023, 24(4), 3479; https://doi.org/10.3390/ijms24043479 - 09 Feb 2023

Cited by 1 | Viewed by 1448

Abstract

The lack of knowledge about the uptake of NPs by biological cells poses a significant problem for drug delivery. For this reason, designing an appropriate model is the main challenge for modelers. To address this problem, molecular modeling studies that can describe the mechanism of cellular uptake of drug-loaded nanoparticles have been conducted in recent decades. In this context, we developed three different models for the amphipathic nature of drug-loaded nanoparticles (MTX-SS-γ-PGA), whose cellular uptake mechanism was predicted by molecular dynamics studies. Many factors affect nanoparticle uptake, including nanoparticle physicochemical properties, protein–particle interactions, and subsequent agglomeration, diffusion, and sedimentation. Therefore, the scientific community needs to understand how these factors can be controlled and the NP uptake of nanoparticles. Based on these considerations, in this study, we investigated for the first time the effects of the selected physicochemical properties of the anticancer drug methotrexate (MTX) grafted with hydrophilic-γ-polyglutamic acid (MTX-SS-γ-PGA) on its cellular uptake at different pH values. To answer this question, we developed three theoretical models describing drug-loaded nanoparticles (MTX-SS-γ-PGA) at three different pH values, such as (1) pH 7.0 (the so-called neutral pH model), (2) pH 6.4 (the so-called tumor pH model), and (3) pH 2.0 (the so-called stomach pH model). Exceptionally, the electron density profile shows that the tumor model interacts more strongly with the head groups of the lipid bilayer than the other models due to charge fluctuations. Hydrogen bonding and RDF analyses provide information about the solution of the NPs with water and their interaction with the lipid bilayer. Finally, dipole moment and HOMO-LUMO analysis showed the free energy of the solution in the water phase and chemical reactivity, which are particularly useful for determining the cellular uptake of the NPs. The proposed study provides fundamental insights into molecular dynamics (MD) that will allow researchers to determine the influence of pH, structure, charge, and energetics of NPs on the cellular uptake of anticancer drugs. We believe that our current study will be useful in developing a new model for drug delivery to cancer cells with a much more efficient and less time-consuming model. Full article

(This article belongs to the Special Issue Nanotechnology-Based Drug Delivery Systems for Cancer Therapy)

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18 pages, 3868 KiB

Open AccessArticle

Dual (pH- and ROS-) Responsive Antibacterial MXene-Based Nanocarrier for Drug Delivery

by Wei-Jin Zhang, Shuwei Li, Yong-Zhu Yan, Sung Soo Park, Anandhu Mohan, Ildoo Chung, Suk-kyun Ahn, Jung Rae Kim and Chang-Sik Ha

Int. J. Mol. Sci. 2022, 23(23), 14925; https://doi.org/10.3390/ijms232314925 - 29 Nov 2022

Cited by 4 | Viewed by 2216

Abstract

In this study, a novel MXene (Ti₃C₂T_x)-based nanocarrier was developed for drug delivery. MXene nanosheets were functionalized with 3, 3′-diselanediyldipropionic acid (DSeDPA), followed by grafting doxorubicin (DOX) as a model drug to the surface of functionalized MXene nanosheets (MXene-Se-DOX). The nanosheets were characterized using scanning electron microscopy, atomic force microscopy (AFM), transmission electron microscopy, energy-dispersive X-ray spectroscopy (EDX), nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, X-ray diffraction, and zeta potential techniques. The drug-loading capacity (17.95%) and encapsulation efficiency (41.66%) were determined using ultraviolet–visible spectroscopy. The lateral size and thickness of the MXene nanosheets measured using AFM were 200 nm and 1.5 nm, respectively. The drug release behavior of the MXene-Se-DOX nanosheets was evaluated under different medium conditions, and the nanosheets demonstrated outstanding dual (reactive oxygen species (ROS)- and pH-) responsive properties. Furthermore, the MXene-Se-DOX nanosheets exhibited excellent antibacterial activity against both Gram-negative E. coli and Gram-positive B. subtilis. Full article

(This article belongs to the Special Issue Nanotechnology-Based Drug Delivery Systems for Cancer Therapy)

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21 pages, 3585 KiB

Open AccessArticle

Carboxymethyl-Dextran-Coated Superparamagnetic Iron Oxide Nanoparticles for Drug Delivery: Influence of the Coating Thickness on the Particle Properties

by Chiara Turrina, Davide Milani, Anna Klassen, Diana M. Rojas-González, Jennifer Cookman, Matthias Opel, Barbara Sartori, Petra Mela, Sonja Berensmeier and Sebastian P. Schwaminger

Int. J. Mol. Sci. 2022, 23(23), 14743; https://doi.org/10.3390/ijms232314743 - 25 Nov 2022

Cited by 11 | Viewed by 2520

Abstract

Carboxymethyl-dextran (CMD)-coated iron oxide nanoparticles (IONs) are of great interest in nanomedicine, especially for applications in drug delivery. To develop a magnetically controlled drug delivery system, many factors must be considered, including the composition, surface properties, size and agglomeration, magnetization, cytocompatibility, and drug activity. This study reveals how the CMD coating thickness can influence these particle properties. ION@CMD are synthesized by co-precipitation. A higher quantity of CMD leads to a thicker coating and a reduced superparamagnetic core size with decreasing magnetization. Above 12.5–25.0 g L⁻¹ of CMD, the particles are colloidally stable. All the particles show hydrodynamic diameters < 100 nm and a good cell viability in contact with smooth muscle cells, fulfilling two of the most critical characteristics of drug delivery systems. New insights into the significant impact of agglomeration on the magnetophoretic behavior are shown. Remarkable drug loadings (62%) with the antimicrobial peptide lasioglossin and an excellent efficiency (82.3%) were obtained by covalent coupling with the EDC/NHS (N-ethyl-N′-(3-(dimethylamino)propyl)carbodiimide/N-hydroxysuccinimide) method in comparison with the adsorption method (24% drug loading, 28% efficiency). The systems showed high antimicrobial activity with a minimal inhibitory concentration of 1.13 µM (adsorption) and 1.70 µM (covalent). This system successfully combines an antimicrobial peptide with a magnetically controllable drug carrier. Full article

(This article belongs to the Special Issue Nanotechnology-Based Drug Delivery Systems for Cancer Therapy)

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22 pages, 5147 KiB

Open AccessArticle

Optimized Apamin-Mediated Nano-Lipidic Carrier Potentially Enhances the Cytotoxicity of Ellagic Acid against Human Breast Cancer Cells

by Shaimaa M. Badr-Eldin, Hibah M. Aldawsari, Usama A. Fahmy, Osama A. A. Ahmed, Nabil A. Alhakamy, Omar D. Al-hejaili, Alhanoof A. Alhassan, Ghadeer A. Ammari, Shouq I. Alhazmi, Raghad M. Alawadi, Rana Bakhaidar, Abdulmohsen J. Alamoudi, Thikryat Neamatallah and Singkome Tima

Int. J. Mol. Sci. 2022, 23(16), 9440; https://doi.org/10.3390/ijms23169440 - 21 Aug 2022

Cited by 4 | Viewed by 1748

Abstract

Ellagic acid has recently attracted increasing attention regarding its role in the prevention and treatment of cancer. Surface functionalized nanocarriers have been recently studied for enhancing cancer cells’ penetration and achieving better tumor-targeted delivery of active ingredients. Therefore, the present work aimed at investigating the potential of APA-functionalized emulsomes (EGA-EML-APA) for enhancing cytototoxic activity of EGA against human breast cancer cells. Phospholipon^® 90 G: cholesterol molar ratio (PC: CH; X₁, mole/mole), Phospholipon^® 90 G: Tristearin weight ratio (PC: TS; X₂, w/w) and apamin molar concentration (APA conc.; X₃, mM) were considered as independent variables, while vesicle size (VS, Y₁, nm) and zeta potential (ZP, Y₂, mV) were studied as responses. The optimized formulation with minimized vs. and maximized absolute ZP was predicted successfully utilizing a numerical technique. EGA-EML-APA exhibited a significant cytotoxic effect with an IC₅₀ value of 5.472 ± 0.21 µg/mL compared to the obtained value from the free drug 9.09 ± 0.34 µg/mL. Cell cycle profile showed that the optimized formulation arrested MCF-7 cells at G2/M and S phases. In addition, it showed a significant apoptotic activity against MCF-7 cells by upregulating the expression of p53, bax and casp3 and downregulating bcl2. Furthermore, NF-κB activity was abolished while the expression of TNfα was increased confirming the significant apoptotic effect of EGA-EML-APA. In conclusion, apamin-functionalized emulsomes have been successfully proposed as a potential anti-breast cancer formulation. Full article

(This article belongs to the Special Issue Nanotechnology-Based Drug Delivery Systems for Cancer Therapy)

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Review

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25 pages, 2650 KiB

Open AccessReview

Anti-Hypoxia Nanoplatforms for Enhanced Photosensitizer Uptake and Photodynamic Therapy Effects in Cancer Cells

by Nkune Williams Nkune and Heidi Abrahamse

Int. J. Mol. Sci. 2023, 24(3), 2656; https://doi.org/10.3390/ijms24032656 - 31 Jan 2023

Cited by 6 | Viewed by 2743

Abstract

Photodynamic therapy (PDT) holds great promise in cancer eradication due to its target selectivity, non-invasiveness, and low systemic toxicity. However, due to the hypoxic nature of many native tumors, PDT is frequently limited in its therapeutic effect. Additionally, oxygen consumption during PDT may exacerbate the tumor’s hypoxic condition, which stimulates tumor proliferation, metastasis, and invasion, resulting in poor treatment outcomes. Therefore, various strategies have been developed to combat hypoxia in PDT, such as oxygen carriers, reactive oxygen supplements, and the modulation of tumor microenvironments. However, most PDT-related studies are still conducted on two-dimensional (2D) cell cultures, which fail to accurately reflect tissue complexity. Thus, three-dimensional (3D) cell cultures are ideal models for drug screening, disease simulation and targeted cancer therapy, since they accurately replicate the tumor tissue architecture and microenvironment. This review summarizes recent advances in the development of strategies to overcome tumor hypoxia for enhanced PDT efficiency, with a particular focus on nanoparticle-based photosensitizer (PS) delivery systems, as well as the advantages of 3D cell cultures. Full article

(This article belongs to the Special Issue Nanotechnology-Based Drug Delivery Systems for Cancer Therapy)

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22 pages, 2499 KiB

Open AccessReview

Microfluidic Approaches for Affinity-Based Exosome Separation

by Eike K. Theel and Sebastian P. Schwaminger

Int. J. Mol. Sci. 2022, 23(16), 9004; https://doi.org/10.3390/ijms23169004 - 12 Aug 2022

Cited by 14 | Viewed by 3316

Abstract

As a subspecies of extracellular vesicles (EVs), exosomes have provided promising results in diagnostic and theranostic applications in recent years. The nanometer-sized exosomes can be extracted by liquid biopsy from almost all body fluids, making them especially suitable for mainly non-invasive point-of-care (POC) applications. To achieve this, exosomes must first be separated from the respective biofluid. Impurities with similar properties, heterogeneity of exosome characteristics, and time-related biofouling complicate the separation. This practical review presents the state-of-the-art methods available for the separation of exosomes. Furthermore, it is shown how new separation methods can be developed. A particular focus lies on the fabrication and design of microfluidic devices using highly selective affinity separation. Due to their compactness, quick analysis time and portable form factor, these microfluidic devices are particularly suitable to deliver fast and reliable results for POC applications. For these devices, new manufacturing methods (e.g., laminating, replica molding and 3D printing) that use low-cost materials and do not require clean rooms are presented. Additionally, special flow routes and patterns that increase contact surfaces, as well as residence time, and thus improve affinity purification are displayed. Finally, various analyses are shown that can be used to evaluate the separation results of a newly developed device. Overall, this review paper provides a toolbox for developing new microfluidic affinity devices for exosome separation. Full article

(This article belongs to the Special Issue Nanotechnology-Based Drug Delivery Systems for Cancer Therapy)

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