Nanoparticles for Brain Drug Delivery

Carla Vitorino, Andreia Jorge, Alberto A.C.C. Pais, Carla Vitorino, Andreia Jorge, Alberto A.C.C. Pais

• Publisher: Jenny Stanford Publishing
• Year: 2021
• ISBN:
  9781000245639
• Edition: 1
• Topic: Medicina
• Subtopic: Biotecnología en medicina

In an era wherein nanotechnology has sparked a huge research interest, brain drug delivery is not an exception. Aiming at fighting several central nervous system (CNS) conditions, tailored nanoparticles open new avenues to address several challenges in the fields of drug delivery and brain targeting. This book gathers contributions from experts in different, complementary fields, having in common their interest in developing new strategies for brain delivery based on nanotechnologies.

The book encompasses general aspects pertaining to fundamental development, including tripartite in silico–in vitro–in vivo approaches. It also covers a diversity of nanomedicines applied in treatment and/or diagnosis and monitoring of CNS disorders. Aspects concerning their translation from the bench to clinical practice are also seamlessly discussed.

This book will inspire readers to discover possible approaches to holistically delivering drugs into the brain. Edited by Carla Vitorino, Andreia Jorge and Alberto Pais, this book will appeal to anyone involved in nanomedicine, pharmaceutics, neurological and cancer therapies, drug delivery research and computational and regulatory sciences.

Part I
FUNDAMENTALS

Chapter 1
Recent Trends in Nanotechnology for Brain Delivery: A Brief Outlook

Carla Vitorino,^a,b,c Andreia Jorge^c and Alberto Pais^c

^a Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000–548 Coimbra, Portugal

^b Centre for Neurosciences and Cell Biology (CNC), University of Coimbra, Faculty of Medicine, Rua Larga, Pólo I, 1st Floor, 3004–504 Coimbra, Portugal

^c Coimbra Chemistry Centre, Department of Chemistry, University of Coimbra, Rua Larga, 3004–535 Coimbra, Portugal [email protected]

Brain targeting still represents a major therapeutic challenge: drug delivery to the brain is strictly regulated by the blood-brain barrier (BBB), which imposes an overwhelming obstacle for many central nervous system (CNS) active drugs. The BBB is responsible for the homeostatic mechanism of defence of the brain against foreign substances, including toxic molecules and pathogens. However, drug penetration is only one among several difficult challenges. These stem from the complexity and heterogeneity of cell brain composition, affecting both the prevalence and the response to simple drug targets, and also the respective pharmacokinetics and stability [1, 2].

The increasing incidence of brain-related pathologies and the hurdles which undermine the development of efficient and effective strategies have pushed both researchers and the pharmaceutical industry to search for novel therapeutic alternatives. Nanotechnology undoubtedly offers a broad bunch of options to circumvent the multiple challenges imposed for brain drug delivery [3].

Recent solutions from nanotechnology encompass a wide diversity of nanocarriers, ranging from organic to inorganic, and systems combining materials from both natures, known as hybrid nanosystems. Synthetic particulate delivery systems (e.g. liposomes, solid lipid matrix nanoparticles, polymeric nanoparticles, micelles, gold, iron oxide particles) can be presented in multiple designs, with different compositions, stabilities and solubilities, supported by flexible and often up-scalable production methods, while offering versatile loading capacities for a variety of therapeutics [4]. However, and despite the evident progress in the development of effective drug delivery nanocarriers, their clinical application still remains conditioned by delivery, targeting and safety concerns [5]. These include unknown tissue interactions and adsorption of serum proteins, resulting in unpredicted outcomes which include rapid clearance, inefficient loading, nonbiodegradability, and essentially a lack of specific and active targeting to the tissue/organ of interest.

To overcome these shortcomings, a variety of advanced surface chemistry engineering strategies have been proposed, directed at either improving stability and circulation or enhancing tissue targeting and cellular uptake. Such approaches take into consideration the overexpressed receptors in cells to mediate the internalisation of specific ligands and their associated therapeutic cargoes. Taking advantage of the cell-type-specific fingerprint, many smart nanosystems have been hierarchically decorated to incorporate specific moieties able to bind to receptor-docking sites. Candidates acting as recognition anchors may include aptamers, antibodies, peptides, proteins, carbohydrates, and small molecules, such as folate and vitamins [6].

Alternatively, carrier cells have been equated as drug delivery vehicles on the basis of their intrinsic tropism toward a site of interest and their capability to release a desired therapeutic agent. Different cargo types can be transported, such as antibodies, therapeutic genes and proteins, microRNA, oncolytic viruses, or even nanoparticles. Some examples include mesenchymal stem cells, macrophages, endothelial cells, or cancer cells [4].

Exosomes, as extracellular vesicles which bud from various cells through spontaneous or inducible biological processes, have also sparked particular interest as a natural, yet nonviral, alternative to synthetic vectors [7, 8]. Notwithstanding their somewhat natural active targeting capabilities and ability to traverse physiological barriers, such as the BBB, issues associated with the use of whole cells for drug delivery can be ascribed to the fact that the cells may differentiate and/or actually trigger pathologies, including cancer and possible metastasis [4].

Driven by these principles, more recently the use of biomimeting materials has become a reality in the form of cell membrane-camouflaged nanoparticles. These biohybrid systems essentially combine the technological advantages of nanomaterials with the stealth and biocompatibility characteristics of, for example, erythrocytes, leukocytes, or stem cell ghosts [9]. Cell ghosts, as nanosize biosystems devoid of their intracellular components, retain, however, the majority of their membrane proteins and lipids, which can be channeled to active or passive targeting [10].

Note, however, that the versatility of nanocarrier systems is not confined to the challenges imposed by intravenous administration. Physiological surrogates, such as the intranasal route, are pointed out as a reliable and direct pathway to surpass the BBB. Indeed, owing to the unique direct connection between the brain and the nasal cavity mediated by the olfactory epithelium, intranasal administration is the only route through which the brain is in connection with the outside environment, thus considerably enlarging the application of nanotechnology for brain delivery [11, 12].

The use of nanoscale systems does not hamper the respective combination with physical methods such as ultrasound, commonly employed to reversibly perturb the BBB and facilitate transport into the brain, allowing a complementary non-invasive boosting strategy for CNS drug delivery [13].

Apart from the therapeutic purposes, nanotechnology can also be fine-tuned to serve diagnosis, giving rise to its application in the theranostic area. Nanotheranostics, by integrating diagnostic and therapeutic functions in a single system, holds the benefits of nanotechnology and opens avenues in oncology and the personalised medicine research field [14].

All these aspects will be detailed and expanded throughout the subsequent chapters.

Acknowledgments

The Coimbra Chemistry Centre (CQC) is supported by the Fundaẹäo para a Ciência e Tecnologia (FCT) through Project UID/QUI/00313/2020. A.F.J. acknowledges FCT, Portugal, for financial support regarding the postdoctoral grant SFRH/BPD/104544/2014.

References

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• 4. Schoen, B., Machluf, M. (2016). Cell ghosts: cellular membranes for drug delivery, in Perspectives in Micro- and Nanotechnology for Biomedical Applications, World Scientific Publishing, pp. 225–273.
• 5. Soares, S., Sousa, J., Pais, A., Vitorino, C. (2018). Nanomedicine: principles, properties, and regulatory issues. Front. Chem., 6, 360.
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• 10. Toledano Furman, N. E., Lupu-Haber, Y., Bronshtein, T., Kaneti, L., Letko, N., Weinstein, E., et al. (2013). Reconstructed stem cell nanoghosts: a natural tumor targeting platform. Nano Lett., 13(7), 3248–3255.
• 11. Vitorino, C., Silva, S., Bicker, J., Falcao, A., Fortuna, A. (2019). Antidepressants and nose-to-brain delivery: drivers, restraints, opportunities and challenges. Drug Discov. Today, 24(9), 1911–1923.
• 12. Mistry, A., Stolnik, S., Illum, L. (2009). Nanoparticles for direct nose-to-brain delivery of drugs. Int. J. Pharm., 379(1),...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Contents
• Preface
• Part I: Fundamentals
• Part II: Nanomedicines
• Part III: Development and Translation
• Index