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Pharmaceutics
Special Issues
Drug Delivery as Molecular Transport through Biological Barriers
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Drug Delivery as Molecular Transport through Biological Barriers

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

Deadline for manuscript submissions: closed (10 August 2022) | Viewed by 14048

Special Issue Editors

Prof. Dr. Milos Kojic

E-Mail Website
Guest Editor
1. Houston Methodist Research Institute, Houston, TX, USA
2. Bioengineering R&D Center Kragujevac, Kragujevac, Serbia
3. Serbian Academy of Science and Arts, Belgrade, Serbia
Interests: drug delivery; computational models; physiological barriers; drug vectors; implant devices; imaging analysis; immunotherapy; microenvironment; intra-tumoral pharmacokinetics
Special Issues, Collections and Topics in MDPI journals
Dr. Arturas Ziemys

E-Mail Website
Guest Editor
Houston Methodist Research Institute, USA
Interests: therapeutic resistance; data analysis; drug delivery; tumor microenvironement; computational modeling; imaging analysis
Dr. Miljan Milosevic

E-Mail Website
Guest Editor
1. Bioengineering R&D Center Kragujevac, Serbia
2. University of Kragujevac, Serbia
3. Metropolitan University, Belgrade, Serbia
Interests: drug delivery; computational models; nanoparticles

Special Issue Information

Dear Colleagues,

All therapeutic delivery strategies have to overcome inevitable physiological barriers in order to transport drugs to cells situated far from the systemic circulation. Therapeutic substances have to permeate multitudes of cells and vascular walls, infiltrate networks of interstitial biopolymers, escape phagocytic cells, and face physico-chemical factors limiting their delivery. The presence of these and other barriers is a fundamental determinant of therapeutic efficacy or therapeutic resistance.

This Special Issue will focus on physiological barriers to drug delivery investigated by various methodological approaches according to their related scientific disciplines. Manuscripts dealing with analytical and computational aspects of drug delivery and physiological barriers are of special interest. Furthermore, the combination of quantitative imaging, data analysis, and experiments to improve the design of drug delivery from implants and drug vectors as well as in immunotherapy is of particular interest.

Prof. Milos Kojic
Dr. Arturas Ziemys
Dr. Miljan Milosevic
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

  • drug delivery
  • computational models
  • physiological barriers
  • drug vectors
  • implant devices
  • imaging analysis
  • immunotherapy
  • microenvironment
  • intra-tumoral pharmacokinetics

Published Papers (4 papers)

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Research

16 pages, 2522 KiB  
Article
Optimised Electroporation for Loading of Extracellular Vesicles with Doxorubicin
by Angus J. Lennaárd, Doste R. Mamand, Rim Jawad Wiklander, Samir EL Andaloussi and Oscar P. B. Wiklander
Pharmaceutics 2022, 14(1), 38; https://doi.org/10.3390/pharmaceutics14010038 - 24 Dec 2021
Cited by 41 | Viewed by 5926
Abstract
The clinical use of chemotherapeutics is limited by several factors, including low cellular uptake, short circulation time, and severe adverse effects. Extracellular vesicles (EVs) have been suggested as a drug delivery platform with the potential to overcome these limitations. EVs are cell-derived, lipid [...] Read more.
The clinical use of chemotherapeutics is limited by several factors, including low cellular uptake, short circulation time, and severe adverse effects. Extracellular vesicles (EVs) have been suggested as a drug delivery platform with the potential to overcome these limitations. EVs are cell-derived, lipid bilayer nanoparticles, important for intercellular communication. They can transport bioactive cargo throughout the body, surmount biological barriers, and target a variety of tissues. Several small molecule drugs have been successfully incorporated into the lumen of EVs, permitting efficient transport to tumour tissue, increasing therapeutic potency, and reducing adverse effects. However, the cargo loading is often inadequate and refined methods are a prerequisite for successful utilisation of the platform. By systematically evaluating the effect of altered loading parameters for electroporation, such as total number of EVs, drug to EV ratio, buffers, pulse capacitance, and field strength, we were able to distinguish tendencies and correlations. This allowed us to design an optimised electroporation protocol for loading EVs with the chemotherapeutic drug doxorubicin. The loading technique demonstrated improved cargo loading and EV recovery, as well as drug potency, with a 190-fold increased response compared to naked doxorubicin. Full article
(This article belongs to the Special Issue Drug Delivery as Molecular Transport through Biological Barriers)
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11 pages, 4598 KiB  
Article
Attenuated Microcirculation in Small Metastatic Tumors in Murine Liver
by Arturas Ziemys, Vladimir Simic, Miljan Milosevic, Milos Kojic, Yan Ting Liu and Kenji Yokoi
Pharmaceutics 2021, 13(5), 703; https://doi.org/10.3390/pharmaceutics13050703 - 12 May 2021
Cited by 3 | Viewed by 1744
Abstract
Metastatic cancer disease is the major cause of death in cancer patients. Because those small secondary tumors are clinically hardly detectable in their early stages, little is known about drug biodistribution and permeation into those metastatic tumors potentially contributing to insufficient clinical success [...] Read more.
Metastatic cancer disease is the major cause of death in cancer patients. Because those small secondary tumors are clinically hardly detectable in their early stages, little is known about drug biodistribution and permeation into those metastatic tumors potentially contributing to insufficient clinical success against metastatic disease. Our recent studies indicated that breast cancer liver metastases may have compromised perfusion of intratumoral capillaries hindering the delivery of therapeutics for yet unknown reasons. To understand the microcirculation of small liver metastases, we have utilized computational simulations to study perfusion and oxygen concentration fields in and around the metastases smaller than 700 µm in size at the locations of portal vessels, central vein, and liver lobule acinus. Despite tumor vascularization, the results show that blood flow in those tumors can be substantially reduced indicating the presence of inadequate blood pressure gradients across tumors. A low blood pressure may contribute to the collapsed intratumoral capillary lumen limiting tumor perfusion that phenomenologically corroborates with our previously published in vivo studies. Tumors that are smaller than the liver lobule size and originating at different lobule locations may possess a different microcirculation environment and tumor perfusion. The acinus and portal vessel locations in the lobule were found to be the most beneficial to tumor growth based on tumor access to blood flow and intratumoral oxygen. These findings suggest that microcirculation states of small metastatic tumors can potentially contribute to physiological barriers preventing efficient delivery of therapeutic substances into small tumors. Full article
(This article belongs to the Special Issue Drug Delivery as Molecular Transport through Biological Barriers)
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15 pages, 5596 KiB  
Article
Seed- and Soil-Dependent Differences in Murine Breast Tumor Microenvironments Dictate Anti-PD-L1 IgG Delivery and Therapeutic Efficacy
by Yan Ting Liu, Shreya Goel, Megumi Kai, Jose Alberto Moran Guerrero, Thao Nguyen, Junhua Mai, Haifa Shen, Arturas Ziemys and Kenji Yokoi
Pharmaceutics 2021, 13(4), 530; https://doi.org/10.3390/pharmaceutics13040530 - 10 Apr 2021
Cited by 3 | Viewed by 3027
Abstract
We sought to determine if Stephen Paget’s “seed and soil” hypothesis of organ-preference patterns of cancer metastasis can explain the development of heterogeneity in a tumor microenvironment (TME) as well as immunotherapeutic delivery and efficacy. We established single-cell-derived clones (clones 1 and 16) [...] Read more.
We sought to determine if Stephen Paget’s “seed and soil” hypothesis of organ-preference patterns of cancer metastasis can explain the development of heterogeneity in a tumor microenvironment (TME) as well as immunotherapeutic delivery and efficacy. We established single-cell-derived clones (clones 1 and 16) from parental 4T1 murine breast cancer cells to create orthotopic primary and liver metastasis models to deconvolute polyclonal complexity cancer cells and the difference in TME-derived heterogeneities. Tumor-bearing mice were treated with anti-PD-L1 IgG or a control antibody, and immunofluorescent imaging and quantification were then performed to evaluate the therapeutic efficacy on tumor growth, the delivery of therapy to tumors, the development of blood vessels, the expression of PD-L1, the accumulation of immune cells, and the amount of coagulation inside tumors. The quantification showed an inverse correlation between the amount of delivered therapy and therapeutic efficacy in parental-cell-derived tumors. In contrast, tumors originating from clone 16 cells accumulated a significantly greater amount of therapy and responded better than clone-1-derived tumors. This difference was greater when tumors grew in the liver than the primary site. A similar trend was found in PD-L1 expression and immune cell accumulation. However, the change in the number of blood vessels was not significant. In addition, the amount of coagulation was more abundant in clone-1-derived tumors when compared to others. Thus, our findings reconfirmed the seed- and soil-dependent differences in PD-L1 expression, therapeutic delivery, immune cell accumulation, and tumor coagulation, which can constitute a heterogeneous delivery and response of immunotherapy in polyclonal tumors growing in different organs. Full article
(This article belongs to the Special Issue Drug Delivery as Molecular Transport through Biological Barriers)
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18 pages, 7910 KiB  
Article
Anti-Tumor Efficiency of Perillylalcohol/β-Cyclodextrin Inclusion Complexes in a Sarcoma S180-Induced Mice Model
by Allan A. Rezende, Rafael S. Santos, Luciana N. Andrade, Ricardo G. Amaral, Matheus M. Pereira, Cristiane Bani, Mo Chen, Ronny Priefer, Classius F. da Silva, Ricardo L. C. de Albuquerque Júnior, Eliana B. Souto and Patrícia Severino
Pharmaceutics 2021, 13(2), 245; https://doi.org/10.3390/pharmaceutics13020245 - 10 Feb 2021
Cited by 10 | Viewed by 2651
Abstract
The low solubility and high volatility of perillyl alcohol (POH) compromise its bioavailability and potential use as chemotherapeutic drug. In this work, we have evaluated the anticancer activity of POH complexed with β-cyclodextrin (β-CD) using three complexation approaches. Molecular docking suggests the hydrogen-bond [...] Read more.
The low solubility and high volatility of perillyl alcohol (POH) compromise its bioavailability and potential use as chemotherapeutic drug. In this work, we have evaluated the anticancer activity of POH complexed with β-cyclodextrin (β-CD) using three complexation approaches. Molecular docking suggests the hydrogen-bond between POH and β-cyclodextrin in molar proportion was 1:1. Thermal analysis and Fourier-transform infrared spectroscopy (FTIR) confirmed that the POH was enclosed in the β-CD cavity. Also, there was a significant reduction of particle size thereof, indicating a modification of the β-cyclodextrin crystals. The complexes were tested against human L929 fibroblasts after 24 h of incubation showing no signs of cytotoxicity. Concerning the histopathological results, the treatment with POH/β-CD at a dose of 50 mg/kg promoted approximately 60% inhibition of tumor growth in a sarcoma S180-induced mice model and the reduction of nuclear immunoexpression of the Ki67 antigen compared to the control group. Obtained data suggest a significant reduction of cycling cells and tumor proliferation. Our results confirm that complexation of POH/β-CD not only solves the problem related to the volatility of the monoterpene but also increases its efficiency as an antitumor agent. Full article
(This article belongs to the Special Issue Drug Delivery as Molecular Transport through Biological Barriers)
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