We are pleased to introduce the collection Frontiers in Medical Technology – Highlights in Nano-Based Drug Delivery 2021/22. This collection will welcome and showcase a selection of high impact articles authored by leaders in the field. The work presented here highlights the broad diversity of research performed across the Nano-Based Drug Delivery section, and aims to put a spotlight on the main areas of interest. This collection aims to further support Frontiers’ strong community by shining a spotlight on our authors' highly impactful research.

Harcourt Butler Technical University

University of Southern California

Faculty of Pharmacy, University of Lisbon

Discover diverse research on nano-based drug delivery methods from renowned authors

. The use of multicellular tumor spheroids in cancer research has been widely explored, and this research topic looks at the issues that need to be considered when switching from bi-dimensional to three-dimensional models for screening protocols. Additionally, the use of hydroxyapatite (HAp) as a bioceramic material for drug delivery and magnetic hyperthermia in the treatment of cancer is discussed, as well as advances in dendrimer nanoparticle drug delivery systems to treat chronic wounds. LIFNano-CD4 has been shown to cross the blood-brain barrier and provide anti-inflammatory efficacy in the brain, and 3D bioprinting is an efficient additive manufacturing technology for fabricating well-defined and clinical-scale relevant 3D scaffolds. The research topic also looks at the engineering and manufacturing of nanomedicines that can cross the blood-brain barrier for non-viral gene therapy of the brain, as well as the potential of finite element (FE) simulation in predicting the printability of a biomaterial. <ul> <li>Multicellular tumor spheroids are widely used in cancer research and this research topic looks at the issues that need to be considered when switching from bi-dimensional to three-dimensional models for screening protocols.</li> <li>The use of hydroxyapatite (HAp) as a bioceramic material for drug delivery and magnetic hyperthermia in the treatment of cancer is discussed, as well as advances in dendrimer nanoparticle drug delivery systems to treat chronic wounds.</li> <li>LIFNano-CD4 has been shown to cross the blood-brain barrier and provide anti-inflammatory efficacy in the brain, and 3D bioprinting is an efficient additive manufacturing technology for fabricating well-defined and clinical-scale relevant 3D scaffolds.</li> <li>The research topic also looks at the engineering and manufacturing of nanomedicines that can cross the blood-brain barrier for non-viral gene therapy of the brain, as well as the potential of finite element (FE) simulation in predicting the printability of a biomaterial.</li> </ul>

Frontiers in Medical Technology

Nano-Based Drug Delivery

Highlights in Nano-Based Drug Delivery 2021/22

Editorial on the Research Topic <a href="https://www.frontiersin.org/research-topics/35332/highlights-in-nano-based-drug-delivery-202122">Highlights in nano-based drug delivery 2021/22</a>We are pleased to introduce the Research Topic Frontiers in Medical Technology – Highlights in Nano-Based Drug Delivery 2021/22. The articles published in this brief collection provide an important contribution to the field of nano-based delivery.The paper Modeling the Three-Dimensional Bioprinting Process of β-Sheet Self-Assembling Peptide Hydrogel Scaffolds, authored by <a href="https://doi.org/10.3389/fmedt.2020.571626">Chiesa and colleagues</a>, describes an interesting approach of extrusion-based three-dimensional (3D) bioprinting. 3D bioprinting is fast changing the field of personalized healthcare offering new approaches and processes for the fabrication of scaffolds, living tissues, unique drug dosage forms, etc. This paper highlights the limitations of the common trial and error approaches, which are frequently used for achieving the desired final features of the designed structures. To address such issue, the authors investigated the potential of finite element simulation in predicting the printability of a biomaterial. Thanks to this study, the authors successfully 3D bioprinted human ear-shaped scaffolds by using self-assembling peptide hydrogels with a poly(vinyl alcohol)–poly(vinyl pyrrolidone) copolymer. This methodology can have a broad applicability, thus further promoting the expansion of 3D bioprinting.Gene therapy has finally climbed the mountain of efforts and has become a real therapy option, with enormous future applications and great expectations. Gene therapy has grown thanks to improvements on gene delivery that takes care of the proper transportation of the genetic material to the target cells via viral or non-viral carriers. <a href="https://doi.org/10.3389/fmedt.2020.602236">Pardridge's</a> review Brain Delivery of Nanomedicines: Trojan Horse Liposomes for Plasmid DNA Gene Therapy of the Brain offers a great overview of the requirements needed for the development of an ambitious project on brain gene therapy. The challenge, as it can be easily understood, is huge owing to the intrinsic difficulties encountered in crossing the blood-brain barrier. Here, you can find a precise analysis of all relevant components that can guide you towards the successful delivery of genetic material to the brain.Another relevant investigation has been conducted by <a href="https://doi.org/10.3389/fmedt.2021.640569">de la Flor and colleagues</a>. In&nbsp;their paper Multiple Sclerosis: LIFNano-CD4 for Trojan Horse Delivery of the Neuro-Protective Biologic “LIF” Into the Brain: Preclinical Proof of Concept, the authors studied the potential of a nanoformulation of the cell growth factor LIF for the treatment of multiple sclerosis. Since such disease still represents an unmet medical need and this study can advance the development of new therapeutic approaches, in which thanks to a nanomedicine properly designed, the bioactive molecule is delivered precisely at the site of action.We hope that you will enjoy the papers contained in this Research Topic, which we hope will inspire your future scientific endeavors.GP and HF wrote the editorial, SK participated as a Research Topic editor. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Editorial: Highlights in nano-based drug delivery 2021/22

Multicellular tumor spheroids are largely exploited in cancer research since they are more predictive than bi-dimensional cell cultures. Nanomedicine would benefit from the integration of this three-dimensional in vitro model in screening protocols. In this brief work, we discuss some of the issues that cancer nanomedicine will need to consider in the switch from bi-dimensional to three-dimensional multicellular tumor spheroid models.

Multicellular tumor spheroids are largely exploited in cancer research since they are more predictive than bi-dimensional cell cultures. Nanomedicine would benefit from the integration of this three-dimensional in vitro model in screening protocols. In this brief work, we discuss some of the issues that cancer nanomedicine will need to consider in the switch from bi-dimensional to three-dimensional multicellular tumor spheroid models.

Multicellular Tumor Spheroids in Nanomedicine Research: A Perspective

The use of biomaterials in medicine is not recent, and in the last few decades, the research and development of biocompatible materials had emerged. Hydroxyapatite (HAp), a calcium phosphate that constitutes a large part of the inorganic composition of human bones and teeth, has been used as an interesting bioceramic material. Among its applications, HAp has been used to carry antitumor drugs, such as doxorubicin, cisplatin, and gemcitabine. Such HAp-based composites have an essential role in anticancer drug delivery systems, including the treatment of osteosarcoma. In addition, the association of this bioceramic with magnetic nanoparticles (MNPs) has also been used as an effective agent of local magnetic hyperthermia. Further, the combined approach of the aforementioned techniques (HAp scaffolds combined with anti-tumor drugs and MNPs) is also an attractive therapeutical alternative. Considering the promising role of the use of bioceramics in modern medicine, we proposed this review, presenting an updated perspective on the use of HAp in the treatment of cancer, especially osteosarcoma. Finally, after giving the current progress in this field, we highlight the urgent need for efforts to provide a better understanding of their potential applications.

The use of biomaterials in medicine is not recent, and in the last few decades, the research and development of biocompatible materials had emerged. Hydroxyapatite (HAp), a calcium phosphate that constitutes a large part of the inorganic composition of human bones and teeth, has been used as an interesting bioceramic material. Among its applications, HAp has been used to carry antitumor drugs, such as doxorubicin, cisplatin, and gemcitabine. Such HAp-based composites have an essential role in anticancer drug delivery systems, including the treatment of osteosarcoma. In addition, the association of this bioceramic with magnetic nanoparticles (MNPs) has also been used as an effective agent of local magnetic hyperthermia. Further, the combined approach of the aforementioned techniques (HAp scaffolds combined with anti-tumor drugs and MNPs) is also an attractive therapeutical alternative. Considering the promising role of the use of bioceramics in modern medicine, we proposed this review, presenting an updated perspective on the use of HAp in the treatment of cancer, especially osteosarcoma. Finally, after giving the current progress in this field, we highlight the urgent need for efforts to provide a better understanding of their potential applications.

Calcium Phosphate-Based Bioceramics in the Treatment of Osteosarcoma: Drug Delivery Composites and Magnetic Hyperthermia Agents

The United States spends billions of dollars to treat chronic wounds each year. Wound healing is complex in nature which involves several intricate multiphase processes that can be delayed for a number of reasons leading to the development of chronic wounds. Wound healing therapies range from topical preparations to surgical repair with treatment options that vary based on other underlying factors like co-infection, age, or co-morbidities such as diabetes. Historically, micelles and liposomes are some of the nanoparticle drug delivery systems explored to treat chronic wounds; however, recent data suggests that dendrimers have shown potential to rival these systems in treating chronic wounds as well as other diseases. This mini review examines advances in dendrimer nanoparticle drug delivery systems to treat chronic wounds.

The United States spends billions of dollars to treat chronic wounds each year. Wound healing is complex in nature which involves several intricate multiphase processes that can be delayed for a number of reasons leading to the development of chronic wounds. Wound healing therapies range from topical preparations to surgical repair with treatment options that vary based on other underlying factors like co-infection, age, or co-morbidities such as diabetes. Historically, micelles and liposomes are some of the nanoparticle drug delivery systems explored to treat chronic wounds; however, recent data suggests that dendrimers have shown potential to rival these systems in treating chronic wounds as well as other diseases. This mini review examines advances in dendrimer nanoparticle drug delivery systems to treat chronic wounds.

Exploring Dendrimer Nanoparticles for Chronic Wound Healing

Multiple sclerosis (MS) is a demyelinating autoimmune disease that attacks the brain, with year-on-year loss of brain volume, starting late teens and becoming manifest late twenties. There is no cure, and current therapies are immunosuppressive only. LIF is a vital stem cell growth factor active throughout life—and essential for health of the central nervous system (CNS), being tolerogenic, myelinogenic, and neuroprotective. Nano-formulation of LIF (LIFNano) using FDA-approved PLGA captures LIF's compound therapeutic properties, increasing potency 1,000-fold when targeted to CD4 (LIFNano-CD4). Moreover, circulating CD4+ lymphocytes are themselves regulated by LIF to express the Treg phenotype, known to release T cell-derived LIF upon engagement with cognate antigen, perpetuating antigen-specific self-tolerance. With the longer-term aim of treating inflammatory lesions of MS, we asked, does LIFNano-CD4 cross the blood–brain barrier (BBB)? We measure pK and pD using novel methodologies, demonstrate crossing of the BBB, show LIF-cargo-specific anti-inflammatory efficacy in the frontal cortex of the brain, and show safety of intravenous delivery of LIFNano-CD4 at doses known to provide efficacious concentrations of LIF cargo behind the BBB.

Multiple sclerosis (MS) is a demyelinating autoimmune disease that attacks the brain, with year-on-year loss of brain volume, starting late teens and becoming manifest late twenties. There is no cure, and current therapies are immunosuppressive only. LIF is a vital stem cell growth factor active throughout life—and essential for health of the central nervous system (CNS), being tolerogenic, myelinogenic, and neuroprotective. Nano-formulation of LIF (LIFNano) using FDA-approved PLGA captures LIF's compound therapeutic properties, increasing potency 1,000-fold when targeted to CD4 (LIFNano-CD4). Moreover, circulating CD4+ lymphocytes are themselves regulated by LIF to express the Treg phenotype, known to release T cell-derived LIF upon engagement with cognate antigen, perpetuating antigen-specific self-tolerance. With the longer-term aim of treating inflammatory lesions of MS, we asked, does LIFNano-CD4 cross the blood–brain barrier (BBB)? We measure pK and pD using novel methodologies, demonstrate crossing of the BBB, show LIF-cargo-specific anti-inflammatory efficacy in the frontal cortex of the brain, and show safety of intravenous delivery of LIFNano-CD4 at doses known to provide efficacious concentrations of LIF cargo behind the BBB.

Multiple Sclerosis: LIFNano-CD4 for Trojan Horse Delivery of the Neuro-Protective Biologic “LIF” Into the Brain: Preclinical Proof of Concept

Non-viral gene therapy of the brain is enabled by the development of plasmid DNA brain delivery technology, which requires the engineering and manufacturing of nanomedicines that cross the blood-brain barrier (BBB). The development of such nanomedicines is a multi-faceted problem that requires progress at multiple levels. First, the type of nanocontainer, e.g., nanoparticle or liposome, which encapsulates the plasmid DNA, must be developed. Second, the type of molecular Trojan horse, e.g., peptide or receptor-specific monoclonal antibody (MAb), must be selected for incorporation on the surface of the nanomedicine, as this Trojan horse engages specific receptors expressed on the BBB, and the brain cell membrane, to trigger transport of the nanomedicine from blood into brain cells beyond the BBB. Third, the plasmid DNA must be engineered without bacterial elements, such as antibiotic resistance genes, to enable administration to humans; the plasmid DNA must also be engineered with tissue-specific gene promoters upstream of the therapeutic gene, to insure gene expression in the target organ with minimal off-target expression. Fourth, upstream manufacturing of the nanomedicine must be developed and scalable so as to meet market demand for the target disease, e.g., annual long-term treatment of 1,000 patients with an orphan disease, short term treatment of 10,000 patients with malignant glioma, or 100,000 patients with new onset Parkinson's disease. Fifth, downstream manufacturing problems, such as nanomedicine lyophilization, must be solved to ensure the nanomedicine has a commercially viable shelf-life for treatment of CNS disease in humans.

Non-viral gene therapy of the brain is enabled by the development of plasmid DNA brain delivery technology, which requires the engineering and manufacturing of nanomedicines that cross the blood-brain barrier (BBB). The development of such nanomedicines is a multi-faceted problem that requires progress at multiple levels. First, the type of nanocontainer, e.g., nanoparticle or liposome, which encapsulates the plasmid DNA, must be developed. Second, the type of molecular Trojan horse, e.g., peptide or receptor-specific monoclonal antibody (MAb), must be selected for incorporation on the surface of the nanomedicine, as this Trojan horse engages specific receptors expressed on the BBB, and the brain cell membrane, to trigger transport of the nanomedicine from blood into brain cells beyond the BBB. Third, the plasmid DNA must be engineered without bacterial elements, such as antibiotic resistance genes, to enable administration to humans; the plasmid DNA must also be engineered with tissue-specific gene promoters upstream of the therapeutic gene, to insure gene expression in the target organ with minimal off-target expression. Fourth, upstream manufacturing of the nanomedicine must be developed and scalable so as to meet market demand for the target disease, e.g., annual long-term treatment of 1,000 patients with an orphan disease, short term treatment of 10,000 patients with malignant glioma, or 100,000 patients with new onset Parkinson&apos;s disease. Fifth, downstream manufacturing problems, such as nanomedicine lyophilization, must be solved to ensure the nanomedicine has a commercially viable shelf-life for treatment of CNS disease in humans.

Brain Delivery of Nanomedicines: Trojan Horse Liposomes for Plasmid DNA Gene Therapy of the Brain

Extrusion-based three-dimensional (3D) bioprinting is nowadays the most efficient additive manufacturing technology to fabricate well-defined and clinical-scale relevant 3D scaffolds, exploiting soft biomaterials. However, trial and error approaches are usually employed to achieve the desired structures, thus leading to a waste of time and material. In this work, we show the potential of finite element (FE) simulation in predicting the printability of a biomaterial, in terms of extrudability and scaffold mechanical stability over time. To this end, we firstly rheologically characterized a newly developed self-assembling peptide hydrogel (SAPH). Subsequently, we modeled both the extrusion process of the SAPHs and the stability over time of a 3D-bioprinted wood-pile scaffold. FE modeling revealed that the simulated SAPHs and printing setups led to a successful extrusion, within a range of shear stresses that are not detrimental for cells. Finally, we successfully 3D bioprinted human ear-shaped scaffolds with in vivo dimensions and several protrusion planes by bioplotting the SAPH into a poly(vinyl alcohol)–poly(vinyl pyrrolidone) copolymer, which was identified as a suitable bioprinting strategy by mechanical FE simulation.

Extrusion-based three-dimensional (3D) bioprinting is nowadays the most efficient additive manufacturing technology to fabricate well-defined and clinical-scale relevant 3D scaffolds, exploiting soft biomaterials. However, trial and error approaches are usually employed to achieve the desired structures, thus leading to a waste of time and material. In this work, we show the potential of finite element (FE) simulation in predicting the printability of a biomaterial, in terms of extrudability and scaffold mechanical stability over time. To this end, we firstly rheologically characterized a newly developed self-assembling peptide hydrogel (SAPH). Subsequently, we modeled both the extrusion process of the SAPHs and the stability over time of a 3D-bioprinted wood-pile scaffold. FE modeling revealed that the simulated SAPHs and printing setups led to a successful extrusion, within a range of shear stresses that are not detrimental for cells. Finally, we successfully 3D bioprinted human ear-shaped scaffolds with in vivo dimensions and several protrusion planes by bioplotting the SAPH into a poly(vinyl alcohol)–poly(vinyl pyrrolidone) copolymer, which was identified as a suitable bioprinting strategy by mechanical FE simulation.