Nanomedicine E-Book
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- Sprache: Englisch
A comprehensive and multidisciplinary guide to nanomaterials-based medicine
Nanomedicine is the study and application of nanomaterials-based medical techniques. In recent years it has very rapidly become indispensable in a huge range of medical contexts, from analysis of extreme life events to diagnosis and treatment of life-threatening intractable diseases, such as cancers and cardiovascular diseases. It has already transformed both research and clinical outcomes in many areas of medicine and promises to continue as the cutting-edge research and clinical area for the next generation of medical specialists.
Nanomedicine: Fundamentals, Synthesis, and Applications constitutes a comprehensive guide to this subfield and its recent advances. Beginning with a brief history of the field and introduction to its core principles, it thoroughly treats recent developments in this vital and ever-growing field. Its multidisciplinary approach equips the reader with a systematic overview of these life-saving developments in medicine.
Nanomedicine readers will also find:
- Edited by a leading researcher with decades of experience in both North America and China
- Detailed treatment of subjects including nanocarriers, nanomaterial bioprobes, multi-function nanodrugs, nanomedicine-mediated immunotherapy and/or physical ablation, and more
- A comprehensive volume treats every facet of the subject
Nanomedicine is a vital resource for biochemists, biomedical engineers, pharmaceutical chemists, physicists, and professionals in the biotechnological industries, as well as for clinicians looking to familiarize themselves with nanomedical techniques and instrumentation.
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Table of Contents
Cover
Table of Contents
Title Page
Copyright
Preface
1 State of the Art in Nanomedicine
1.1 Intractable Diseases and Development of the Related Novel Therapy and Medicines
1.2 Key Features of Nanomedicines
1.3 Nanotechnology Translational Nanomedicine: Emergence and Progress
1.4 Interdisciplinary Features of Nanomedicines: Multi-mode and Multi-function Features Promoting Nanomedicine-mediated Immunotherapy and/or Physical Field Ablation Therapy for Subversive Therapy
1.5 Future Development of Nanomedicines by Coupling Advanced Biomedicines (Including Biochemistry and Biophysics), Modern Physicochemical Technologies, and Artificial Intelligence Technology
References
2 Fundamentals in Nanomedicine
2.1 Design Theory of Nanomedicines
2.2 Progress in the Controlled Synthesis of Nanomaterials
2.3 Progress in the Surface Modification and Functionalization of Nanomaterials for Nanomedicines
References
3 Nanomedicine for Antitumors
3.1 Introduction
3.2 Liposomal Nanoparticles
3.3 Polymeric Nanoparticles
3.4 Inorganic Nanoparticles
3.5 Mixture (Hybrid) Nanoparticles
3.6 Cell Membrane Coating Nanotechnology
3.7 Challenges and Current Limitations
3.8 Conclusions
References
Note
4 Nanomedicine for the Treatment of Nervous System Diseases
4.1 Concepts and Types of Nanomedicines for Nervous System Diseases
4.2 Therapeutical Methods for Nervous System Diseases and Features of Current Nanomedicines
4.3 Synthesis Methods and Typical Examples (Including Clinical Trial) of Polymer-based Nanomedicines for Nervous System Diseases
4.4 Inorganic-based Nanomedicines: Synthesis Methods and Typical Application (Including Clinical)
4.5 Metallic-based Nanomedicines: Synthesis Methods and Typical Application (Including Clinical)
4.6 Multifunctional Nanomedicines for Nervous System Diseases
References
5 Nanomaterial Translational Nanomedicine for Anti-HIV and Anti-bacterial
5.1 Concepts, Anti-HIV Theory, and Types and Features of Current Nanomedicines
5.2 Polymer-based Nanomedicines: Synthesis Methods and Typical Application
5.3 Inorganic-based Nanomedicines: Synthesis Methods and Typical Application
5.4 Metallic-based Nanomedicines: Synthesis Methods and Typical Application
5.5 Multi-functional (Target) Nanomedicines
5.6 Future Development
References
6 Nanomedicine for Next-generation Dermal Management
6.1 Introduction
6.2 Nano-biomaterials-based Therapeutics for Wound Healing
6.3 Nano-biomaterials for Imaging and Monitoring of Cutaneous Wounds
6.4 Conclusion and Future Outlook
Acknowledgments
References
7 Nanomedicine for Targeting Delivery of Gene and Other DNA/RNA Therapies Based Viruses Engineering
7.1 Targeting Delivery of Gene Therapies to the Tumors
7.2 Targeting Delivery of Gene-based Nanovaccines to the Spleen
7.3 Targeting Delivery of Gene-based Nanovaccines to the LNs
7.4 Targeting Delivery of Gene-based Nanomedicines to the Liver
7.5 Targeting Delivery of Gene-based Nanomedicines to the Lung
7.6 Targeting Delivery of Gene-based Nanomedicines to the Brain
References
8 Nanomedicine for Bio-imaging and Disease Diagnosis
8.1 Concepts, Types, and Features of Current Nanoprobes
8.2 Synthesis Methods
8.3 Typical Application Examples in the Disease Diagnosis and Study of Biological Events
8.4 Future Development
References
9 Magnetic Nanoparticles and Their Applications
9.1 Introduction
9.2 Classification of Magnetic Nanoparticles
9.3 Biomedical Applications
9.4 Conclusion and Outlook
References
10 Nanomedicine-mediated Immunotherapy
10.1 Immune System and Immune Response
10.2 Mechanism of Tumor Immunotherapy
10.3 Mechanism of Nanomedicine-enhancing Immunotherapy
10.4 Immunological Applications of Nanomedicines
10.5 Summary and Outlook
References
11 Nanomedicine-mediated Ultrasound Therapy
11.1 Concept, Therapy Theory, and Devices
11.2 Nanomedicine Synthesis with Ultrasound Field Response
11.3 Application Examples
References
12 Nanomedicine-mediated Photodynamic and/or Photothermal Therapy
12.1 Photodynamic and Photothermal Mechanism for Anti-cancer
12.2 Nanomaterial-based PSs (Nano-PSs) for PDT
12.3 Photodynamic and Photothermal Synergistic Therapy
12.4 Opportunities and Challenges
12.5 Summary
References
Note
13 Nanomedicine-mediated Pulsed Electric Field Ablation Therapy
13.1 Introduction
13.2 Concept, Therapy Theory, and Devices
13.3 Synthesis of Nanomedicine with Electric Field Response
13.4 Application Examples
13.5 Conclusion
References
Note
14 Nanomedicine-mediated Magneto-dynamic and/or Magneto-thermal Therapy
14.1 Concepts, Treatment Theories, and Methods
14.2 Treatment Theories and Methods
14.3 Magnetic Field-responsive Nanomedicine Synthesis
14.4 Applications
References
15 Nanomedicine-mediated Radiotherapy for Cancer Treatment
15.1 Concept, Therapy Theory, and Devices
15.2 Nanomaterials as Radiosensitizers for Radiation Therapy
15.3 Nanomaterials Delivering Radioisotope for Internal Radioisotope Therapy
15.4 Nanomedicine Synthesis with Radio/Nuclear Radiation Response
15.5 Conclusion and Prospects
References
16 Nanomedicine Conjugating with AI Technology and Genomics for Precise and Personalized Therapy
16.1 Concept
16.2 Genomics of Nanomedicine
16.3 Artificial Intelligence Technology in Nanomedicine Development
16.4 Artificial Intelligence Facilitates Precise and Personalized Nanomedicine Based on Genomics
References
17 Microfluidic Conjugating AI Platform for High-throughput Nanomedicine Screening
17.1 Introduction
17.2 Microfluidic Technologies for Medicine Development
17.3 Microfluidic Preparation of Nanomedicines
17.4 Microfluidic High-throughput Drug Screening
17.5 AI-assisted Microfluidic Development of Nanomedicine
17.6 Conclusions and Perspectives
References
Note
Index
End User License Agreement
List of Tables
Chapter 1
Table 1.1 Working modes of the currently developed multi-modal ablation ther...
Table 1.2 Working modes, therapeutical characteristics, applications, repres...
Table 1.3 Achievements of multiple physical field ablation and/or multi-mode...
Chapter 2
Table 2.1 Different targeting moieties on nanoparticle surfaces and extent o...
Chapter 5
Table 5.1 Comparison of four methods.
Chapter 8
Table 8.1 Comparison of biological imaging techniques.
Chapter 9
Table 9.1 Tunable magnetic properties important for biomedical applications ...
Chapter 13
Table 13.1 Advantages and disadvantages of various pulse waveform generators...
Chapter 15
Table 15.1 A brief summary of the response of normal cells to ionizing radia...
Table 15.2 A brief summary of the major milestones in cancer radiotherapy.
Table 15.3 A brief summary of some therapeutic α-emitters delivered by nanom...
Table 15.4 A brief summary of some therapeutic β-emitters delivered by nanom...
Table 15.5 A brief summary of some therapeutic Auger-emitters delivered by n...
List of Illustrations
Chapter 1
Figure 1.1 (a) Scale comparison of nanometer and some typical biomolecules a...
Figure 1.2 (a) Historical timeline of major developments of nanomedicine. EP...
Chapter 2
Figure 2.1 Drug-targeting strategies. Stimuli-responsive drug delivery.
Figure 2.2 Different microfluidic flows of two-phase flow.
Figure 2.3 Schematic illustration of integrating patient-specific nanomateri...
Figure 2.4 Biological synthesis of NPs shows distinct advantages over physic...
Figure 2.5 Classical DLVO theory of colloid stability.
Figure 2.6 Influence of PEG density on serum protein adsorption to gold nano...
Chapter 3
Figure 3.1 The enhanced permeability and retention (EPR) impact in the tissu...
Figure 3.2 Diagram showing the miniature extruder used to make nanoliposomes...
Figure 3.3 Solvent evaporation method.
Figure 3.4 Solvent diffusion method.
Figure 3.5 Salting out method.
Figure 3.6 Nanoprecipitation method.
Figure 3.7 Ion gelation method.
Figure 3.8 A novel metal-organic nanocomposite material serves as a synergis...
Figure 3.9 Administration of NpRg3 effectively prevents changes to the ileoc...
Figure 3.10 Au@CoFeB nanoparticles and Au@CoFeB–Rg3 nanomedicines show multi...
Figure 3.11 The safety and efficacy of ferroptosis-apoptosis combination tre...
Figure 3.12 Diagram illustrating the structural component, the NFPR preparat...
Figure 3.13 (a) Nanomedicine microcapsule production using a multijunction d...
Chapter 4
Figure 4.1 Schematic illustration of DOX@PEG-Ag2S nanomedicine and real-time...
Figure 4.2 Schematic diagram of rGO-AuNRVe in vivo.
Figure 4.3 (a) Synthesis route for nanocomposites. (b) Selectively trigger t...
Figure 4.4 Schematic illustration of L-Arg@PCN@Mem for gas therapy and sensi...
Figure 4.5 Effective and targeted human orthotopic glioblastoma xenograft th...
Chapter 5
Figure 5.1 Schematic representation of drug-carrying systems through lysosom...
Figure 5.2 Lymphatic uptake mechanisms.
Figure 5.3 Simple condensed phase separation.
Figure 5.4 Polymer micelles.
Figure 5.5 (a) Divergence and (b) convergence.
Chapter 6
Figure 6.1 Overview of representative nano-biomaterial strategies for cutane...
Figure 6.2 (a) Illustration of the presumed action mechanism of the α-Fe
2
O
3
-...
Figure 6.3 (a) Schematic illustration of the nanobridging concept for gluing...
Figure 6.4 (a) Schematic illustration of PEG-MoS
2
construction which acts as...
Figure 6.5 (a) Schematic illustration of the simultaneous self-protecting de...
Figure 6.6 (a) Chemical structures of polymers utilized in this study. (b) S...
Figure 6.7 (a) SEM images of 250 nm gratings and unpatterned polydimethylsil...
Figure 6.8 (a) Experimental setup to investigate the generation of an inflam...
Figure 6.9 (a) The fabrication process of bidirectionally grown zinc oxide n...
Figure 6.10 (a) Preparation and schematic illustration of the SiO
2
-Cy-Van na...
Figure 6.11 (a) Schematic illustration of the topical application of NanoFla...
Chapter 7
Figure 7.1 Nanocarriers targeting delivery to tumors are mainly divided into...
Figure 7.2 Targeting delivery of gene based nanovaccines to dendritic cells ...
Figure 7.3 LNP binding with ApoE tends to be accumulated in the liver after ...
Figure 7.4 Targeting delivery of gene based nanomedicines to the lung can be...
Figure 7.5 Targeting delivery of gene based nanomedicines to the brain can b...
Chapter 8
Figure 8.1 LSPR real color images of (a(i) Au@CoFeB NPs and b(i) Au@CoFeB–Rg...
Figure 8.2 Solution color under ultraviolet illumination of CdSe nanocrystal...
Figure 8.3 (a) Typical TEM image of the Fe
3
O
4
NPs; the
inset
shows a histogr...
Figure 8.4 Magnetic resonance imaging (MRI) effects of ultra-small FeZn
x
@Zn(...
Figure 8.5 Chemical reduction method.
Figure 8.6 Schematic presentation of the SPMP (a), design of the PMS (b), an...
Figure 8.7 Structure of a multifunctional QD probe.
Figure 8.8 Sensitivity and multicolor capability of QD imaging in live anima...
Figure 8.9 (a) Real-time in vivo NIR fluorescence images after intravenous i...
Figure 8.10 TEM images of Au nanocages (AuNCs) with average edge lengths of ...
Figure 8.11 Schematics of GNT-assisted PA/PT molecular diagnostics and thera...
Chapter 9
Figure 9.1 Statistics on the articles focusing on the application of magneti...
Figure 9.2 (a) Hard magnetic nanoparticles and (b) soft magnetic nanoparticl...
Figure 9.3 The magnetic moment structure of magnetic nanoparticles.
Figure 9.4 Schematic representation of various heterostructure nanoparticles...
Figure 9.5 The curve of magnetic properties with nanoparticle diameter.
Figure 9.6 (a) Schematic of demagnetization field lines of a magnetized elli...
Figure 9.7 The lattice structure of Fe
3
O
4
with doping ions (such as Mn
2+
Figure 9.8 Schematic illustration of exchange–coupling between ferromagnet c...
Figure 9.9 Schematic illustration of magnetic resonance imaging.
Figure 9.10 Schematic illustration of magnetic hyperthermia.
Figure 9.11 Schematic illustration of targeted drug delivery.
Figure 9.12 Schematic illustration of the application of MNPs in neuromodula...
Chapter 10
Figure 10.1 Immune organizations of human beings.
Figure 10.2 Mechanisms of tumor immunotherapy.
Figure 10.3 Development history of tumor immunotherapy.
Figure 10.4 Transforming “cold tumors” into “hot tumors” to overcome immune ...
Figure 10.5 Scheme illustrations of currently nano drug carriers such as dru...
Figure 10.6 The three Es of cancer immunoediting are elimination, equilibriu...
Figure 10.7 (a) STING-NPs enhance intracellular uptake of cGAMP and, in resp...
Figure 10.8 Schematic of liposomal subunit nanovaccine for anti-SARS-CoV-2....
Figure 10.9 (a) Schematic illustration of the synthesis of PEGylated liposom...
Figure 10.10 (a) Schematic description of the preparation of M/CpG-ODN-TRP2-...
Chapter 11
Figure 11.1 A diagram of the microbubble cavitation phenomenon caused by cha...
Figure 11.2 Classification of nanomedicines.
Figure 11.3 (a) Focused classification of ultrasound transducers. (b) Common...
Figure 11.4 Principle of ultrasound-mediated delivery of nanomedicines in mi...
Chapter 12
Figure 12.1 The mechanism of photodynamic and photothermal therapy.
Figure 12.2 Combination of different therapy methods with PDT and PTT.
Chapter 13
Figure 13.1 Summary of NDDS for “co-encapsulation” approach in chemoimmunoth...
Figure 13.2 Schematic of pulse generator based on single transmission line....
Figure 13.3 Schematic diagram of Blumlein pulse generator.
Figure 13.4 Schematic of pulse power system.
Figure 13.5 MedPulser® system.
Figure 13.6 Nanoknife system: (a) IRE generator; (b) bipolar IRE prob.(c...
Figure 13.7 (a) RD® steep nanosecond pulse generator.(b) Ruidao Medical’...
Figure 13.8 Schematic diagram of e synthesis of multimode nanomedicine and t...
Figure 13.9 Temperature-programmed microfluidic process for the synthesis of...
Figure 13.10 Chemical reaction process of the synthesis of the Au@CoFeB NPs....
Figure 13.11 (a) Wide-viewed TEM image (the inserted image is HR-TEM image w...
Figure 13.12 (a) Wide-viewed TEM image of the Au@CoFeB NPs. (b) HR-TEM image...
Figure 13.13 (a) The high-angle annular dark field (HAADF) STEM image and (b...
Figure 13.14 (a) XRD pattern of the Au@CoFeB NPs suggesting the fcc Au and b...
Figure 13.15 (a) Wide view TEM image of Au@CoFe(B)–Rg3 NMs (the inserted are...
Figure 13.16 LSPR real color images of (a, i) Au@CoFeB NPs and (b, i) Au@CoF...
Figure 13.17 Au@CoFe NPs (a) and Au@CoFe–Rg3 (b) in vitro MRI imaging effect...
Figure 13.18 Au@CoFe NPs (a) and Au@CoFe–Rg3 (b) study on cytotoxicity of di...
Chapter 14
Figure 14.1 Magnetic heat therapy apparatus.
Figure 14.2 Magnetothermal effect: spin entropy changes in excitation and de...
Figure 14.3 Application of magnetic heating in biomedicine. (a) Magnetotherm...
Figure 14.4 Toxic nanoparticles cause cell damage.
Figure 14.5 (a) In vivo experimental scheme. (b) Major central nervous syste...
Chapter 15
Figure 15.1 Interactions of X-rays with high-
Z
elements and the correspondin...
Figure 15.2 Physical and biochemical radiosensitization mechanism of high-
Z
-...
Figure 15.3 Perspective views of (a) the molecular structure of the Au
8
NCs a...
Figure 15.4 (a) Schematic illustration of synthesis of the CY-PSMA-1-Au
25
NCs...
Figure 15.5 Results of in vivo cancer RT experiments carried out using femal...
Figure 15.6 Schematic illustration of possible events that may occur when ph...
Figure 15.7 Schematic illustration of the rational design of the PLGA
-SS-
D@B...
Figure 15.8 Schematic illustration of the design of multifunctional integrat...
Chapter 16
Figure 16.1 Schematic of machine learning steps for supervised learning. Mac...
Figure 16.2 Schematic representation of the simultaneous multiobjective opti...
Figure 16.3 Artificial intelligence-assisted real-time dynamic computation a...
Chapter 17
Figure 17.1 (a) Four major steps involved in soft lithography and three majo...
Figure 17.2 Schematic of various microfluidic device geometries (a) T-juncti...
Figure 17.3 (a) Convection-based method: (left) (right)
Y
junction, (right) ...
Figure 17.4 Process of microfluidic drug screening based on organ-on-a-chip....
Figure 17.5 AI assisted microfluidic development of nanomedicine.
Guide
Cover
Table of Contents
Title Page
Copyright
Preface
Begin Reading
Index
End User License Agreement
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Nanomedicine
Fundamentals, Synthesis, and Applications
Edited by Yujun Song
Editor
Prof. Yujun SongUniversity of Science andTechnology BeijingCenter for Modern Physics TechnologySchool of Mathematics and Physics30 Xueyuan RoadHaidian DistrictBeijing 100083China
Cover Image: © Olemedia/Getty Images
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Print ISBN: 978-3-527-34863-3ePDF ISBN: 978-3-527-83038-1ePub ISBN: 978-3-527-83039-8oBook ISBN: 978-3-527-83040-4
Preface
“The finest thoroughbred horse cannot travel ten paces in one leap, but the sorriest nag can go a ten days’ journey. No accumulation of steps, can’t lead to thousand miles” by Hsun-Tzu in Encouraging to Learn. Since the highly biocompatible liposome nanostructures and silicon polymer-based nanocarriers have been developed in 1960s for drug loading and safe transportation and for prolonged drug lasting, respectively, nanomaterials and nanotechnology translational medicine starts its long march. With unremitting efforts of millions of scientists, engineers, and graduates for almost half a century, nanomedicines ushered in a blowout in academic studies and clinical application after 2010s through the long-term interdisciplinary innovation of physics, chemistry, biology, medicine, life science, and information technology. Their biological effects and therapeutical mechanism of nanomaterials have been revealed gradually, such as enhanced permeability retention (EPR) effects, immunological effects, metaloptosis (e.g. ferroptosis, cuproptosis), enzyme-like function, and the enhanced therapeutical effects by the interaction with varieties of high-energy particles or physical fields.
Benefit from the progresses in physics, chemistry, biology, medicine, pathology, functional materials, biomedical engineering, life science, and nanotechnology, nanomedicines have been developed from single function as drug carriers or encapsulation to multifunctions (e.g. diagnosis, imaging, therapy, monitoring, and intelligent feedbacking) and multi-modality (e.g. chemotherapy, immunotherapy, physical field ablation, high energy particle, or electromagnetic wave radiation). These nanomedicines can be constructed from organics, inorganics, or composites with single components or multi-hierarchy microstructures to realize multi-targeting functions: detection, diagnosis, and therapy. Recently, nanomedicines of multifunction and multi-modality termed as nanotheranostics and nanotherapeutics have been further developed as smart nanomedicines, or intelligent nanomedicines by conjugating some biomarkers for specific active molecules or cells to these nanomedicines. Hitherto, varieties of nanomedicines have been designed and synthesized for intractable disease treatment, such as tumors or cancers, rheumatoid arthritis, cerebrovascular diseases (e.g. stroke, cerebral thrombosis, myocardial infarction), neural diseases (e.g. Parkinson, Alzheimer’s, depression), recurrent and infectious skin diseases (particularly relating to blood, endocrine, and immunity), and highly contagious and lethal infectious diseases (e.g. HIV, COVID-19), and so on. Many of them have been approved by FDA, EMA, or the state food and drug administration of the relating countries for clinical trials and some of them have been commercialized to serve patients. Furthermore, as these multi-modality nanomedicines are mediating to varieties of new physical therapy (e.g. nanosecond pulsed electric fields, high-intensity focus ultrasound, pulsed or alternating magnetic field, ultrashort pulsed laser radiation, γ- or β-ray radiation, and fast neutron fragmentation irradiation) and immunotherapy, many innovative combined therapies can be developed for subversive therapeutical effects, particularly for these intractable diseases. Coupling with their diagnosis, imaging, monitoring, and intelligent feedbacking and expert consulting functions, smart nanotheronaustics have also been developed. In addition, the recently developed artificial intelligence generation content (AIGC) or machine learning technologies have been successfully used in the design and microstructure optimization of multi-mode nanomedicines. It shall be expected to address some fundamental and clinical application issues in the novel therapeutical effects of nanomedicines (e.g. quantum biomedical effects) and the coupling of nanomedicines with multi-physical fields for next generation of subversive therapies. The coupling of nanomedicines with AIGC will accelerate the discovery of novel nanomedicines or quantum medicines and their clinical translation, instrumentation of nanomedicines mediating multi-physical field coupling ablation, serving more and more patients and defending human life and health.
This monograph will try to summarize the above progresses in the nanomedicines systematically and comprehensively. Chapter 1 gives an introduction of the state of the art of nanomedicines by revealing their history, development, current state, and future prospect. Chapter 2 will give a brief fundamental on the design and fabrication of nanomedicines. From Chapters 3–6, some specific nanomedicines will be discussed for some intractable disease treatment based on some detailed examples. Chapters 7 and 10 will summarize the development of nanomedicines with some desired physicochemical or biological properties for unique diagnostic or therapeutical functions. Then some typical combined therapies via nanomedicines medicating physical field ablation will be discussed from Chapters 11–15. Finally, nanomedicine conjugating with AI technology and genomics for precise and personalized therapy and one creative technology for nanomedicine screening or microfluidic platform conjugating to AI will be summarized in Chapters 16 and 17, respectively.
We know that it is impossible to include all progresses and aspect of the rapid blooming and sunshine nanomedicines and the related fields in one monography. We hope that this book will contribute to the research and teaching of readers interesting in this vivid field. We also hope that this monograph can play a key role of tossing out a brick to get a jade gem, attracting more scientists, engineers, and students to join into this never-ending field full of perspectives in fundamental academic researches, applied technologies, and clinical trials. Best wishes that all scholars in this field can achieve more and more. Therefore, we will feel gratified if only this book can give readers some clues on learning and thinking of this interesting field and promote its scientific, technological, and clinical development.
Finally, I dedicate this monograph to my family (my father and mother: Mr Sigan Song and Ms Xiuyun Meng; and my daughter and son, Xinran Song and Haoran Song) for their great support and encouragement in editing and writing this book.
June 2024
Yujun Song
Beijing, China
1State of the Art in Nanomedicine
Yujun Song1,2,3 and Wei Hou1
1University of Science and Technology Beijing, Center for Modern Physics Technology, School of Mathematics and Physics, 30 Xueyuan Road, Haidian District, Beijing 100083, China
2Zhengzhou Tianzhao Biomedical Technology Company Ltd., Zhengzhou New Technology Industrial Development Zone, 7B-1209 Dongqing Street, Zhengzhou 451450, China
3Key Laboratory of Pulsed Power Translational Medicine of Zhejiang Province, Hangzhou Ruidi Biotechnology Company Ltd., Room 803, Bldg. 4, 4959 Yuhangtang Road, Cangqian Street, Hangzhou 310023, China
1.1 Intractable Diseases and Development of the Related Novel Therapy and Medicines
Lots of people get sick now and then in their lives, reducing their quality of life and even threatening their lives. Many diseases not only cause great suffering for people themselves but also for their families and then of the whole society, particularly for those intractable diseases, such as tumors or cancers, rheumatoid arthritis, cerebrovascular diseases (e.g. stroke, cerebral thrombosis, myocardial infarction), neural diseases (e.g. Parkinson’s, Alzheimer’s, depression), recurrent and infectious skin diseases (particularly relating to blood, endocrine, and immunity), and highly contagious and lethal infectious diseases (e.g. HIV, COVID-19), and so on. Among them, cerebrovascular diseases are the first killers of people, particularly for those more than 50 years old. There were about 1.79 million people in 2016 who died of these kinds of diseases all over the world, about 31% of global causes of death, according to the statistics of the World Health Organization (WHO). Cardiovascular outpatients in China are already more than 0.29 billion (B). Nearly three million people die from cardiovascular and cerebrovascular diseases in China every year, about 51% of the whole causes of death. Cerebrovascular diseases are the fifth cause of death in 2016, with about 373 deaths per 1 M people. In addition, these kinds of diseases preserve features of high suddenness, high disability rate (about 75% of the surviving patients have varying degrees of loss of labor ability and 40% are severely disabled), high recurrence rate, and more multiple complications (e.g. coronary heart disease, myocardial infarct, vascular dementia, subarachnoid hemorrhage, respiratory tract infection, and sudden deafness). China has entered an aging society like other developed countries (e.g. Japan) even though China is still a developing country. The population of coronary artery disease (CAD) in China has increased from 2.27 M in 2016 to 2.53 M in 2020, with a compound annual growth rate of 2.7%. It was said that China’s precision percutaneous coronary artery therapy (PCI) market has increased from ∼$25.7 M in 2016 to ∼101.4 M in 2020, with a compound annual growth rate of ∼ 40.8%. The global market scale of PCI also shows a growth trend, which was $9.49 B in 2019 and was expected about $13.26 B in 2025 with a compound annual growth rate of ∼ 5.4% (https://www.163.com/dy/article/HPGQBS2R051481OF.html; https://wenku.baidu.com/view/933bb2d7f624ccbff121dd36a32d7375a417c6c4.html?_wkts_=1711608332102&bdQuery=2023%E7%BB%8F%E7%9A%AE%E5%86%A0%E7%8A%B6%E5%8A%A8%E8%84%89%E6%B2%BB%E7%96%97%E5%85%A8%E7%90%83%E5%B8%82%E5%9C%BA%E8%A7%84%E6%A8%A1).
Although cancers are the second killers of people, next to cerebrovascular diseases, the pain and burden of patients caused by cancers far outweigh the former due to their characteristics of chronic redundant diseases. It is said that there were about 19.29 M new cases of cancers, among which there were 10.06 M male cases and 9.23 M female cases according to the statistics in 2020. There were about 9.96 M death cases, including 5.53 M male cases and 4.43 M female cases. It is expected that there will be more than 21 M new cases in 2030 [1–3]. There are about 4.82 M and 2.37 M new cases of cancers, and about 3.21 M and 0.64 death cases of cancers, in China and the United States, respectively [1]. Partially thanks to innovative drugs and therapies promoted by medical technology, the overall trend of death cases of cancers in the United States is accelerated down since 1991 [1]. It is predicted that the new cases and death cases in 2023 will be continuously reduced by 410 K and 30 K compared with those in 2022. However, in China, the new cases and death cases of cancers in 2022 increased by 250 K and 210 K compared with those two years earlier (2020), and the 2022 death/new incidence rate in China is far more than that in United States (67% versus 27%) [1]. The death cases of lung cancers is the first among all death cases in China, and then the summed death cases of liver and pancreatic cancers. Particularly, the cases of liver cancers in China are almost half of the cases in the world. For many cases, cancers were found to be mostly the terminal stage [4–6]. While, thanks to vigorous anti-smoking measures in the United States, the first death case is breast cancer, not lung cancer, in the United States. The survival rates for some special cancers in China are lower than those in the United States, particularly for breast cancers and colorectal cancers. It is also said that cancer prognosis in China is much worse than that in the United States. China needs to make more efforts to provide effective cancer treatment and improve universal health coverage. New medicine and therapy of high anti-cancer efficiency are extremely urgent currently, especially for China. At the same time, the global market of anti-tumor medicine has increased to $192.2 B in 2022 with a compound annual growth rate of ∼12.7% while in China, the sales of anti-tumor drugs have been showing a steady growth trend in recent years. The market size of anti-tumor drugs reached $28.2 B in 2020 and will have an estimated compound annual growth rate of ∼16.1% from 2020 to 2025.
As for hyperuricemia and gout, there were about 1.03 billion (B) outpatients all over the world and about 0.18 B in China in 2022. The global market for gout medicine was about $3.0 B. The gout medicine market in China will grow rapidly in the future, which is expected to be about $1.54 B in 2030. China has been known as the country with the largest population of diabetes in the world. The total number of people related to diabetes exceeded 260 million in 2018, including 114.39 M diabetes outpatients and 148.70 M pre-diabetes population. It is forecasted that the number of diabetes people will reach 320 M, which will create a huge market for diabetes medicine, with a potential scale expected to reach $19.3 B.
There are four types of neural diseases: absence of symptoms, release of symptoms, irritation and shock, such as Parkinson’s, Alzheimer’s, Depression, and Huntington’s diseases. There are more than 0.1 B people more than 15 years old with various mental disorders in China, among which there are about 16 M patients with severe mental disorders and most of the rest are people with mental or behavioral disorders such as depression or autism. These kinds of illnesses not only torture patients but also haunt their families for a long time. Particularly, they preserve some certain psychological infectivity (e.g. resulting in mass suicide groups), leading to great social harm. Developing these kinds of drugs for anti-mental disorders has to overcome the obstacle of passing the blood–brain barrier (BBB). It is more difficult for these drugs into nerve cells to break through the protective membranes of dendrites, myelin sheaths, axons, terminals, etc.
Clearly, fighting these intractable diseases is a long and arduous task for human beings, whose key is to develop diagnosis methods for early disease identification, innovative drugs, and subversive therapies. Starting from this century, medicine and health care entered into a rapid transformation period promoted by the interdisciplinary crossover of life science, biology, biophysics, biochemistry, nanotechnology, and information technology [7, 8]. As a result, many creative medicine or medical technologies sprout recently, such as personalized medicine, precise medicine, nanomedicine, and lots of innovative therapies, such as gene therapy (e.g. mRNA, DNA), targeting therapy (e.g. cell targeting, tumor microenvironment targeting), immunotherapy (e.g. PD1, PD-L1, vaccine, CAR-T,), new physical field ablation therapy (e.g. nanosecond pulsed electrical field (nsPEF) ablation), new physicochemical therapy (e.g. ferroptosis, cuproptosis, photothermal therapy, photodynamic therapy, magnetothermal therapy, magnetodynamic therapy), and heavy particle radiation therapy (e.g. proton beam radiation, neutron scattering radiation, boron neutron capture therapy) [7–21].
Particularly, nanomedicines, which are translated from some functional nanomaterials, deal with nanoscale matters that can be used in biomedicine or biomedical engineering as bioprobes for the detection of biomolecule, organelle, cells or tissues, or as biosensors for the diseases or pathological metabolism diagnosis, or special drugs for some disease treatment or life function regulation. Based on nanodrugs and nanomedical engineering, lots of disruptive solutions have been advanced for the treatment of intractable diseases, such as anti-tumor nanomedicines [22], nanodrugs for rheumatoid arthritis [23], efficient nanodrugs for nerve or brain diseases by overcoming brain–blood barriers [10, 24], and oral administration nanodrugs for anti-HIV at low dosage [25]. Why does nanomedicine have so many special and powerful functions in disease diagnosis and therapy?
1.2 Key Features of Nanomedicines
There are several critical features of nanomaterials for their translation into special and efficient drugs and therapies. First, as shown in Figure 1.1a,b, most nutrition molecules and key functional molecules in the cell microenvironment range from molecule size to nanoscale (e.g. H2O, glucose, phospholipid, protein, antibody, antigen, DNA, RNA). The cross-membrane transportation sizes for small molecules are usually less than 10 nm, which are better if less than 6 nm, and the best ones for each component are 2–3 nm or less (Figure 1.1a, the red dotted circle) [26]. Nanoscale materials can be controlled and synthesized by matching to the nanoscale range of the key biological macromolecules (e.g. protein transport pathways, lysosome, centriole, ribosome) very well. Once their surfaces are modified similarly to those biomolecules (e.g. full of –OH ligands, amino acid side groups, glucose, lipids), they can preserve invisibility to the immune system and behave like zymogen during transportation. Second, sizes of organelles and majority of microstructures formed in cell membranes and organelles usually range from 30 nm (e.g. ribosome) to 10 μm (Figure 1.1a, the dotted pink circle, Figure 1.1c). Except that the nonmembrane structured ribosomes are 15–30 nm, the other organelles are generally ranging from 100 nm to 1.0 μm of mitochondria (the pink dotted circle in Figure 1.1a). As for the cells or bacteria for the motion space of nanomaterials and organelles, their sizes range from more than 1 μm for common bacterial to the smaller cells (i.e. red blood cells), and then at most up to less than 1 mm for the human eggs or frog cells (Figure 1.1a, the green dashed circle). The sizes for endocytosis and exocytosis for macromolecules, such as varieties of RNA, DNA, or proteins, range from several nanometers to several hundreds of nanometers or larger [27–29]. Three kinds of membrane transporting channels (i.e. voltage gates, ligand gates, and pressure activation channels) are all in the nanoscale [28, 29]. These size features of organelles and microstructures of cells provide enough free motion space for nanomaterials less than 10 nm and/or their aggregates less than 1.0 μm to exert their functions. As these nanomaterials are less than 10 nm, they can be surface-modified and functionalized easily by conjugating to some biomolecules and organelles, which facilitates their cross-membrane transportation and interaction with some certain organelles, and then targeting certain fine microstructures of organelles. Even they aggregate to several 10 nm or several 100 nm after biomolecule functionalization due to the strong interaction (e.g. coupling, crosslinking, salt bridges) or weak molecule interaction (e.g. van der Waals forces, hydrogen bonds), they can cross-membrane via endocytosis and exocytosis out or into cells and then lysis into nanometer or sub-nanometer effective components by special biomolecules or other cell microenvironment parameters (e.g. lysosomes, pH). Since they can be constructed with much similar surface properties and microstructures as those biomaterials in organisms, they can successfully avoid most of attacks from immunogenicity or autoimmunity, which can last their retention in organisms, leading to their unique enhanced permeability and retention (EPR) effect together with their high permeability [30–32].
Figure 1.1 (a) Scale comparison of nanometer and some typical biomolecules and cells.
Source: Adapted from Beijing Liuzhi Information Technology Co., Ltd./http://www.360doc.com/showweb/0/0/1102300150/last accessed December 28, 2023.
The other small illustrations are original; (b) biomolecules and functional microstructures in cell membranes; and (c) organelles and microstructures in one single cell.
Clearly, due to their size effects and flexible surface modification and biomolecule functionalization, they show high biocompatibility and EPR effect as they interact with organs, tissues, cells, and organelles, which also benefit for them to overcome BBB for enhanced drug delivery to special focus in special organs or tissues and cells (e.g. brain or spinal, nerve cells, thrombus [preventing atherosclerosis]) [10,33–35]. Particularly for those nanoparticles no more than 6 nm, better for 2–3 nm, they preserve much high bioactivity for efficiency-enhanced curative effect for treatment of tumors, cerebrovascular diseases, neural disease, etc. After they finish their bioactivity, they can be cleared via both urinary system and fecal system, which endows them high biosafety [10, 26, 36].
Nanomedicines can be constructed from organics, inorganics, or composites with single components or multi-hierarchy microstructures to realize some targeting functions: detection, and/or diagnosis, and/or therapy. Usually, their core parts can be ranged from 1.0 to 100 nm, which can be assembled into several hundreds of nanometers or even into several micrometers. Broadly, those with nanometers or even micrometers by assembly of subnanometer components can be generally called nanomedicines. Recently, many multi-mode nanomedicines that preserve functions of detection, imaging, diagnosis, and therapy have been developed or called nanotheranostics and nanotherapeutics [8, 37, 38], which can be further developed as smart nanomedicine, or intelligent nanomedicine if some biomarkers for special molecules or cells are conjugated with these nanomedicines [39].
1.3 Nanotechnology Translational Nanomedicine: Emergence and Progress
Nanotechnology has developed rapidly over the past several decades and nanotechnology translational nanomedicine entered into a blowout development stage by coupling with other biomedical technology and artificial intelligence since 2015 [8, 10, 22, 27, 37,40–58], as shown in Figure 1.2. Up to now, they have constructed many exciting contributions to the treatment of intractable diseases, such as cancers [7, 22, 114, 118], the rheumatoid arthritis [23], or the collagen-induced arthritis [107], nerve or brain diseases [10, 24], anti-HIV [25], cerebrovascular diseases [34, 42], and tissue regeneration (e.g. spinal cord regeneration [128]), skin diseases (e.g. diabetic wound healing) [129–133], as well as precise diagnosis of many special diseases and tracking some key biological processes as ultrasensitive visible bioprobes [83, 98,134–149]. Figure 1.2 gives the historical timeline of major developments of nanomedicines, revealing a gradually developing process for nanoscale materials translational medicine since the first nanoscale medicine, or liposome nanostructures was published in 1964, which were constructed by phospholipids nanoemulsion used as drug carriers to encapsulate readymade low molecule medicine or drugs not compatible with body liquids [59, 114]. In 1964, silicon polymer of high biocompatibility was also developed into nanocarriers for prolonged drug lasting time [70]. The first organic nanodrug entering the technical level was Gris (Griseofulvin)-PEG (polyethylene glycol) oral tablet contenting submicro griseofulvin particles with ultra-high absorption rate, which was applied and issued in 1970 [150]. Langer and Folkman reported the first polymer nano-system for sustained controlled release of ionic molecules and macromolecules in 1976 [60]. In 1986, the EPR effect of nanoparticles was revealed, which is a unique vascular phenomenon for selective concentration of nanoscale agents in tumor or lesion tissues and can greatly increase the utilization efficiency of drugs [32, 61, 62]. For this goal, drugs with long retention time during circulation was desired. However, some negative effects during the drug circulation, such as destruction of immune response and cellular microenvironment factors (e.g. phagocytosis of macrophages, protein corona), have to be addressed by surface modification and using materials of high biocompatibility, hydrophilicity, and biodegradability [118,151–153]. Therefore, long-circulating poly(lactic acid)-co-poly(ethylene glycol) (PLGA-PEG) copolymers-based drugs (e.g. PLGA-PEG encapsulating RNAi or genes) were developed in 1994 by Langer et al. since PLGA-PEG copolymers are of high biocompatibility and hydrophilicity [74]. However, active targeting is correspondingly of much importance when the tissue accumulation of drugs does not depend on EPR [154] or when the delivery of therapeutic agents requires active transcytosis of physiological barriers such as the intestinal mucosa or the BBB [155–157]. Therefore, many studies focused on the development of active targeting drugs and then the concept of active nanoparticle targeting was introduced in the 1970s [71, 72]. In 1976, some synthesized nanodrugs with active targeting functions made their way into clinical trials [30]. The liposomal doxorubicin (Doxil) nanodrugs of active targeting tumors were approved by FDA in 1995, showing greatly enhanced efficiency in cancer treatment [63, 114]. This is encouraging for the field of cancer nanomedicine. Then NP albumin-bound paclitaxel (nab-paclitaxel; Abraxane) became the second class of nanomedicines for long circulation to be approved by FDA in 2005 [63, 114] and commercialized, such as polymeric micelle paclitaxel (Genexol-PM) was successfully marketed in Korea in 2007 [158]. The nab platform enables formulation of hydrophobic drugs while largely mitigating the need to use toxic excipients, and then the regulatory filing for the approval of Vyxeos was projected in late 2016 [114]. Encouraged by the successful commercialization of Abraxane by addressing the enhanced retention time of drugs by the nanoscale strategy, the first targeted siRNA polymeric NPs (CALAA-01) were approved and entered into clinical trials in 2008 [50, 159]. Up to now, there are many targeting nanodrugs developed with controlled release including typical examples of targeted liposomes (for example, HER2) and single-chain variable fragment (scFv)-targeted liposome (MM-302) [160], the first targeted and controlled-release polymeric NP (BIND-014) [161], and the first targeted siRNA NPs (CALAA01) [50, 114, 162]. Simultaneously, the inorganic nanodrugs contenting 15 nm iron oxide particles were also approved as specific drugs for treatment of anemia in 1974 by FDA, following which many inorganic nanodrugs contenting gold, silver, iron oxides, silicon oxides, and titanium oxide nanoparticles have been gradually approved for clinical study by FDA [26, 114].
Figure 1.2 (a) Historical timeline of major developments of nanomedicine. EPR, enhanced permeability and retention; FDA, US Food and Drug Administration; nab, nanoparticle albumin-bound; NP, nanoparticle; PLGA-b-PEG: poly(D,L-lactic-co-glycolic acid)-b-poly(ethylene glycol); PRINT, particle replication in nonwetting template; siRNA, small interfering RNA; HIV, human immunodeficiency virus; QBET, quantum biological tunnelling for electron transfer. (Scheme modified from Figure 1 in the key reference [114] and literatures for the main progress published before 2015 and other related figures clipped from key references for the major progresses in nanoenzymes [66], ferroptosis [117], NPs awaken immune cells anti-cancer as antigen [56, 73], the immune abscopal effect [49], reprogramming immune cells [45, 115, 118], artificial anti-body or nanovaccines [46, 55, 116,119–121], nanoenzymes catalyzing to produce ROS to promote cancer cell apoptosis [95, 122], nanomedicine with multi-mode imaging [41, 89, 98] or targeting and regulation of sub-cellular organelles [27] and tumor microenvironment [41, 101, 123, 124], oral anti-cancer hydrogel-encapsulating nanomedicines [43, 111, 112], cuproptosis anti-cancer mechanism reveal and other T (transition)-metalloptosis therapy confirmed [76,89–94], smart nanodrug systems confirmed [10, 39, 40, 55, 82, 101, 110, 113,125–127] and quantum effects in biology confirmed and forming quantum medicine [9,83–88], etc., montage with permitted copyright.)
(b) The magnified scheme showing nanomedicine mediated multi-physical field (e.g. nanosecond–femtosecond electromagnetic (EM) field, high-intensity focus ultrasound (HIFU), microsecond–picosecond high-energy pulsed electric field, alternative/rotation/pulsed high-intensity magnetic field) ablation on single cells with controlled release and multi-modal therapeutical effects.
Besides the enhanced circulation time in body, the design and synthesis of nanodrugs have to consider how to avoid the immune response before they can be transported into the targeted lesion or cells. Many strategies were invented including the previous methods using materials of high biocompatibility, hydrophilicity, and biodegradability [118, 151]. Based on the direct bionics, cell membrane-coated NPs were further developed to construct cell membrane cloaking nanodrug aggregates by loading nanomedicine into the void cells (e.g. red blood cell) [79, 163, 164]. These cell membrane-coating nanodrug systems can efficiently evade immune response since surface characteristics of these cell membrane-coating nanodrugs are almost the same as those of healthy living cells [79, 163, 164]. During the development of nanodrugs, studies on EPR effects and the related biological mechanism of drugs continue to be paid attention to as their sizes are reduced to nanoscale. For these studies, many multi-mode nanobioprobes, such as protein biomarkers published in 2014 and the imaging agent of ferumoxytol in 2015, have been developed for predicting EPR effects and nanotherapeutic responses, which promotes the progress of nanodrugs with long retention time and active targeting. Together with the gradual realization of multi-functions of nanodrugs, these studies finally led to the emergence of new fields of precise nanomedicine [8, 27], smart nanomedicine [40], and nanotheranostics [37, 42, 165]. According to the therapy effect analysis on nearly 350 kinds of new drugs, contenting nanomaterials submitted for FDA certification from 1970 to 2015 by FDA Drug Evaluation and Research Center in the United States (CDER), the application cases of nanodrugs increased gradually in the past 20 years, among which some have been used to serve people for the treatment of many intractable diseases (e.g. cancers, stroke, Parkinson’s, Alzheimer’s) [166].
With the progress of nanomedicine and their processing technologies (e.g. synthesis, structures and function characterization, multi-functionalization and clinical practice), the related biological mechanism on their fundamental biomedical effects has been deeply revealed, particularly the discovery of nonapoptotic forms of cell death of iron-based nanoparticles, termed as ferroptosis that can significantly promote death of tumor cells, by Dixon et al. [117]. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. It has been confirmed that the small molecule ferrostatin-1 is a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes like glutamate, erastin inhibits cystine uptake by the cystine/glutamate antiporter, creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration for some neurodisease treatments [117]. Since 2016, a research frenzy on ferroptosis in tumor treatment was sparked and many transition metal-based medicines or nanomedicines have been found preserving similar nonapoptotic forms of cell death [94, 122,167–169].
In 2022, the biological mechanism of copper-induced cell death was successfully revealed by Tsvetkov et al. [94]. Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. In human cells, copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. Tsvetkov et al. found that copper-dependent death occurred by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron–sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms. Cell death is an essential, finely tuned process that is critical for the removal of damaged and superfluous cells. Multiple forms of programmed and nonprogrammed cell death have been identified, including apoptosis, ferroptosis, and necroptosis. Using genetically modified cells and a mouse model of a copper overload disorder, the researchers report that excess copper promotes the aggregation of lipoylated proteins and links mitochondrial metabolism to copper-dependent death. Lipoylation determines sensitivity to copper-induced cell death. It can be proposed that Cu-based medicines preserve great promise in tumor cell treatment if they can be precisely targeted into the tumor cells.
With the investigation of the biomedical function of varieties of transition metal-based nanomedicines (e.g. Fe, Co, Cu, Au, Mn, and their compounds or alloys), their enzyme-like mechanism for disease treatment become more and more clear, which can catalyze many key molecule pathways (e.g. reactive ROS, glutamate) using nanomedicines based on the NPs of the transition metals, which can produce similar nonapoptotic forms of cell death in the cancer treatment as ferroptosis or cuproptosis [41, 94, 117, 170, 171], which can be reasonably termed as transition-metalloptosis [90]. Since almost all these nanomedicines preserve the enzyme-like catalyzing functions, which was further defined as a new research arena: nanoenzymes, recently [41, 58, 66, 95, 96, 104,108–110,172–175].
The research field of nanoenzymes has seen exponential growth over the past few years since the term was coined in 2016. This unique modality of cell death, driven by metal-dependent catalysis of some key biological reactions (e.g. ROS, glutamate, phospholipid peroxidation), is regulated by multiple cellular metabolic pathways, including produce of ROS; redox homeostasis; metal handling; mitochondrial activity; and metabolism of key amino acids, lipids, and sugars, in addition to various signaling pathways relevant to disease.
With the gradual reveal of the biomedical effects and their fundamental therapeutic mechanism, and the breakthrough in the controlled preparation methods and the administration technologies of nanomedicine, nanomedicine ushered in a blowout of development since 2016, as shown in Figure 1.2. Particularly, besides nanoenzyme functions [41, 58, 66, 95, 96, 104,108–110,172–175], many of them have played key roles in the overcome of multi-drug-resistant (MDR) during cancer treatment [176–180], in the development of innovative immunotherapy by the reveal of their immunological effects for nanoimmunotherapy [27, 37, 40, 47, 89, 110, 114, 118, 124, 168,181–183].
MDR is a frequently encountered thorny issue as using traditional or even some innovative drugs to treat many diseases, particularly for some persistent infectious diseases and difficult miscellaneous diseases (e.g. cancers), which impedes the successful treatment of targeting diseases [176–180]. Developing novel long-circulating, self-assembled core–shell nanoscale coordination polymer (NCP) nanoparticles that efficiently deliver multiple therapeutics with different mechanisms of action to enhance synergistic therapeutic effects is an innovative strategy to overcome this multi-drug-resistant issue [179]. For example, Lin et al. invented NCPs code liver chemotherapeutics and siRNAs to eradicate tumors of cisplatin-resistant ovarian cancer in 2016 [178]. These NCP particles contain high payloads of chemotherapeutics cisplatin or cisplatin plus gemcitabine in the core and pooled siRNAs that target MDR genes in the shell. The NCP particles possess efficient endosomal escape via a novel carbon dioxide release mechanism without compromising the neutral surface charge required for long blood circulation and effectively downregulate MDR gene expression in vivo to enhance chemotherapeutic efficacy by several orders of magnitude. By silencing MDR genes in tumors, self-assembled core–shell nanoparticles suggest a more effective chemotherapeutic treatment for many challenging cancers [178].
1.4 Interdisciplinary Features of Nanomedicines: Multi-mode and Multi-function Features Promoting Nanomedicine-mediated Immunotherapy and/or Physical Field Ablation Therapy for Subversive Therapy
Tumor immunotherapy has become one of the key innovative methods in tumor treatment and many immunotherapy drugs (e.g. PD-1, PD-L1, CTLA-4) and therapy. (e.g. cart-T) have been developed recently. However, existing cancer immunotherapy drugs work in only 20%–30% of patients [44, 73], particularly for those patients with solid tumor. In some cases, even when the checkpoint molecules are blocked, there are too few active T cells around to sound the immune alarm, says Jedd Wolchok, a cancer immunotherapy expert at the Memorial Sloan Kettering Cancer Center in New York City [73]. Additionally, the key reason is that tumors do not display enough of the T cell’s targets, so-called tumor antigens, on their surface. However, nanoparticles and their functionalized species can behave similar to antigens as they enter into bodies [44, 73, 184]. The immunological mechanism of nanomedicine has been studied intensively for the treatment of tumors in the past decade. Results indicate that nanomedicines preserve intensive immune abscopal effects and have great potential as artificial antigens to activate and train immune cells [185], and they can even reprogram cancer cells or immune cells to reshape the tumor immune microenvironment [37,46–49, 51, 184, 186, 187]. It is said that tumor cells are usually produced every day in our body due to a variety of causes, which will not lead to cancer if they can die through their routine apoptosis themselves or be cleaned by our immune system [47, 48, 113,188–192]. However, tumor cells are smart and can escape from our immune system since they can disguise themselves by releasing some signals or chemicals to let immune cells confirm that they are healthy cells, and then suppress the secretion function of immune cells not to release the corresponding cytokines killing cancer cells [47, 48, 54, 113, 189, 190, 193]. The immunological abscopal effect of nanomedicines was revealed in 2017 by Min et al. [49]. One function of nanomedicines on the immune system is to activate or awaken immune cells, called an immune agonist [44, 73, 178, 194], such as using the paclitaxel nanoparticles to awaken immune system to fight against cancer studied by Tang et al. [194]. In 2016, Lin et al. developed self-assembled core–shell NCP nanoparticles that efficiently delivered multiple therapeutics with different mechanisms of action to enhance synergistic therapeutic effects for ovarian cancer treatment [44]. These NCP NPs contained high payloads of chemotherapeutics cisplatin or cisplatin plus gemcitabine in the core and pooled siRNAs that target multi-drug-resistant (MDR) genes in the shell [44].
Some physical therapies, such as radiation therapy [44, 73] and electrical field therapy [13–15, 195, 196], can break tumor cells to expose some antigens. Therefore, the self-immune systems of some patients can be activated to produce immune response effects similar to immunotherapy after some physical therapy [15, 44, 178, 197, 198]. Based on this phenomenon, Lin et al. from the University of Chicago invented photosensitive ultra-small nanodrugs for tumor treatment, which can ignite the immune responses for some tumors insensitive to immunotherapy by coupling them with radiation therapy [44, 73]. The recent progress suggests that these nanodrug-mediating immunotherapies and/or physical field treatments are expected to enter into clinical trials, which have become the best partner in the field of immunotherapy [15, 37, 44, 73, 178,197–199].
Another immunological function of nanomedicines was to reprogram immune cells to recognize cancer cells advanced in 2018 by Roth et al. [115] and Yang et al. [200], such as reprogramming the function and specificity of human T cells with nonviral genome targeting for anti-cancer therapy [115]. This strategy has been modified for the development of Parkinson’s disease therapy using nanoparticles, such as electromagnetized gold nanoparticles mediating direct lineage reprogramming into induced dopamine neurons for the treatment of Parkinson’s [10].
At the same time, some artificial antibodies (vaccines) have been developing, with active targeting functions [46]. In 2018, Cao and Wang developed a conformational engineering method to create an NP-based artificial antibody, denoted “Goldbody,” through conformational reconstruction of the complementary-determining regions (CDRs) of natural antibodies on gold NPs (AuNPs) [46]. Upon anchoring both terminals of the free CDR loops on AuNPs, the “active” conformation of the CDR loops can be reconstructed by tuning the span between the two terminals, endowing these inorganic NPs the original specificity. Two Goldbodies have been created by this strategy to specifically bind with hen egg white lysozyme and epidermal growth factor receptor, with apparent affinities several orders of magnitude stronger than that of the original natural antibodies. As a result, it is possible to create protein-like functions on these much more stable metallic NPs in a protein-like way, namely by tuning flexible surface groups to the correct conformation, which will finally build up a category of Goldbodies that can target different antigens and thus be used as substitute for natural antibodies in various applications [46]. The first approved anti-body nanodrug Cabiliv (Caplacizumab-Yhdp) was approved by the European Union and then commercially launched for clinical use in 2018, which became the first nano anti-body drug for the treatment of allergic purpura (Henoch-Schonlein syndrome, HSS) in the world. (https://www.sohu.com/a/252250535_119250;https://www.vodjk.com/news/180904/1503187.shtml: Cabiliv™ [caplacizumab] approved in Europe for adults with acquired thrombotic thrombocytopenic purpura [aTTP]; Sanofi gets EU OK for Ablynx flagship drug Cabiliv). This drug was then approved by FDA in the United States in February 2019 (https://www.sohu.com/a/252250535_119250; https://www.drugs.com/history/cablivi.html). Since then, nanomedicines not only with more intimate to immunological effects but also with multiple-therapy functions and multi-targeting functions (e.g. cancer cells, organelles, or tumor microenvironment) have been developed forming a novel field of nano-immunotherapy up to now [47, 48, 51, 57, 101, 118,182–184]. If readers need more details on the immunological effects of nanomedicines, Chapter 10 in this monograph can be referred to.
Simultaneously, coupling of nanomedicines to some advanced biophysical or biochemical methods for subversive combined therapies has been on the way for difficult miscellaneous diseases [27, 37, 40–42, 47, 58, 89, 110, 114, 118, 124, 165, 168, 181–183, 201–203]. Besides their biomedical functions (e.g. immunological effects, enzyme-like functions), nanomedicines constructed by nanohybrids conjugating to varieties of biochemical drugs or preparation, preserve unique physicochemical characteristics and can simultaneously interact with several physical fields (e.g. electrical field, magnetic field, optical field, ultrasound field, electric–magnetic field) [37,46–48, 51, 186, 187]. Multi-mode therapy and diagnosis based on these multi-functional nanomedicine-mediated physical field ablation and/or the corresponding molecule imaging and bioprobe function have been developed recently into one novel medical methodology with both diagnosis and therapy functions, or nanotheranostics [37, 42]. Particularly, nanotheranostics as these multi-mode nanomedicines coupling with physical field ablation preserve greatly enhanced therapeutical effects and in situ precise diagnosis functions for treatment of varieties of intractable diseases by comparing with their counterparts (either physical field ablation or solely nanomedicine), many of which have been implemented in the clinical trial [37].
