Nanoarchitectonics for Smart Delivery and Drug Targeting

Nanoarchitectonics for Smart Delivery and Drug Targeting

Alina Maria Holban

Department of Microbiology and Immunology, Faculty of Biology & Research

Institute of the University of Bucharest, Bucharest, Romania

Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, Bucharest, Romania

Alexandru Mihai Grumezescu

Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, Bucharest, Romania

Table of Contents

Cover

Title page

Copyright

List of Contributors

Preface

Part 1: Smart Delivery

1: Therapeutic Nanostructures: Application of Mechanical Engineering in Drug Delivery

Abstract

1. Introduction

2. Application of Electromagnetism in Drug Delivery

3. Application of Ultrasonic Waves in Drug Delivery

4. Simulation Methods for Dispersion of Nanoparticles in Drug Delivery Systems

5. Conclusions

2: Nanoarchitectured Biomaterials: Present Status and Future Prospects in Drug Delivery

Abstract

1. Introduction

2. Liposomes

3. Dendrimers

4. Aquasomes

5. Nanoparticles

6. Nanogels

7. Nanoemulsions

8. Carbon Nanotubes

9. Quantum Dots

10. Conclusions

3: Smart Nanopolysaccharides for the Delivery of Bioactives

Abstract

1. Introduction

2. Structural Basis for Smartness of Nanopolysaccharides

3. Fabrication of Polysaccharide Nanostructures

4. Polysaccharide Nanostructures in the Delivery of Therapeutics

5. Conclusions

4: Drug-Delivery Applications of Cellulose Nanofibrils

Abstract

1. Background

2. Preparation and Methods

3. Drug Delivery and Other Pharmaceutical Applications of CNFs

4. Toxicology of CNFs

5. Conclusions

5: Nanoarchitectured Polysaccharide-Based Drug Carrier for Ocular Therapeutics

Abstract

1. Introduction

2. Barriers in Ophthalmic Therapeutics

3. Nanotechnology in Ocular Drug Delivery

4. Polysaccharide Nanocarrier in Ocular Drug Delivery

5. Physicochemical Properties of Polysaccharide Nanocarrier

6. Preparation of Polysaccharide Nanocarrier

7. Polysaccharide Nanoparticles and the Anterior Section of the Eye

8. Polysaccharide Nanoparticles and the Posterior Segment of the Eye

9. Polysaccharide Nanoparticles for Gene Therapies

10. Future Prospects

11. Conclusions

6: Current Polyesteric Systems for Advanced Drug Delivery

Abstract

1. Introduction

2. Chemistry of Biodegradable Polyesters

3. Biocompatibility and Regulatory Status

4. Applications

5. Limitations of Polyesters in Pharmaceutical Drug Delivery

6. Future Prospects

7: Nanobiomaterials Architectured for Improved Delivery of Antimalaria Drugs

Abstract

1. Introduction

2. Nanobiomaterials in Drug Delivery

3. Conclusions

Acknowledgment

8: Formulation of Innovative Hybrid Chitosan/TiO2- and Chitosan/SiO2-Based Drug-Delivery Systems

Abstract

1. Introduction

2. Innovative Hybrid Chitosan/TiO2-and Chitosan/SiO2

3. Drug-Delivery Systems

4. Conclusions

Acknowledgments

9: Lanthanide Ions Doped Upconversion Nanomaterials: Synthesis, Surface Engineering, and Application in Drug Delivery

Abstract

1. Mechanism for Upconversion Emission

2. Upconversion Nanoparticles: Dopants and Hosts

3. Enhancement for UC Luminescence

4. Controllable Synthesis of UCNPs

5. Surface Engineering

6. UCNPs-Based Systems for Drug Delivery

7. Conclusions and Future Perspectives

Acknowledgments

10: Nanocomposite Drug Carriers

Abstract

1. Introduction

2. Porous/Hollow Nanovehicles for Anticancer Drug Delivery

3. Hydrogel Contact Lens for the Delivery of Ophthalmic Drugs

4. Hydrogel Film as Wound Dressings in Drug-Delivery Systems

5. Conclusions and Future Outlook

11: Lipid Nanoparticle Formulations for Enhanced Antituberculosis Therapy

Abstract

1. Introduction

2. Limitations of Conventional Antitubercular Therapy

3. Limitations of Oral Delivery of First-Line Antitubercular Drugs

4. Need and Novel Strategies for Antitubercular Drug Delivery

5. Lipid Nanoparticle Formulations

6. Solid Lipid Nanoparticles

7. Nanostructured Lipid Carriers

8. Production Procedure of LNFs at Laboratory Scale

9. Role of LNFs in Antitubercular Drug Delivery

10. Rationale for Using LNFs in Antitubercular Therapy

11. Future Translational Approach

12. Conclusions and Future Perspectives

Acknowledgments

Disclosures/Conflict of Interest

Abbreviations

12: Relevant Aspects on Peptide Delivery from Nanostructured Therapeutic Systems

Abstract

1. Introduction

2. Therapeutic Significance of Peptides in the Treatment of Diseases

3. Limitations of Peptides and Routes of Administration to Succeed the Therapeutics

4. Aspects of Preformulation

5. Drug-Delivery Systems for Peptides

6. Future Perspectives

13: Nanoarchitectured Mesoporous Silica-Based Drug-Delivery Systems: Toward Perfect Nanomedicine

Abstract

1. Introduction

2. Synthesis and Functionalization

3. Pharmacokinetics of MSNs

4. Multifunctionality of Mesoporous Silica Particles

5. Conclusions and Outlook

Acknowledgments

14: Recent Advances in Self-Emulsifying Drug-Delivery Systems for Oral Delivery of Cancer Chemotherapeutics

Abstract

1. Introduction

2. Self-Emulsifying Drug-Delivery Systems: Compositions and Ingredient Selection

3. Mechanisms for Enhancing Oral Bioavailability Using SEDDS Formulations

4. Advances in SEDDS Formulations

5. SEDDS for Oral Delivery of Chemotherapeutic Agents

6. Combinatorial Chemotherapy Using Self-Emulsifying Drug-Delivery Systems

7. Conclusions

15: Scientometric Overview in Nanobiodrugs

Abstract

1. Overview

2. Anticancer Nanobiodrugs

3. Other Nanobiodrugs

4. Conclusions

Part 2: Drug Targeting

16: Polymer: Lipid Hybrid Nanostructures in Cancer Drug Delivery: Successes and Limitations

Abstract

1. Introduction

2. Polymer–Lipid Hybrid Nanostructures

3. Preparation Methods of PLH

4. Factors Affecting Formation of PLH Nanoparticles

5. Applications of PLH in Cancer Therapy

6. Conclusions and Future Scope

Abbreviations

17: Carbon Nanotubes: A Promising Carrier for Drug Delivery and Targeting

Abstract

1. Introduction

2. Types of CNTs

3. Synthesis of CNTs

4. Purification

5. Properties

6. Functionalization

7. Drug-Loading Mechanisms and Cellular Uptake of CNTs

8. Breakdown Mechanism of CNTs in the Body

9. Targeted Drug Delivery by CNTs

10. Conclusions

18: Polymeric Nanoparticles as siRNA Drug Delivery System for Cancer Therapy: The Long Road to Therapeutic Efficiency

Abstract

1. Introduction

2. Structure and Characteristics of Polymers

3. Formulation of Polyplexes

4. Physicochemical Characterization

5. Stability of Polyplexes

6. Blood Stability After Systemic Injection

7. Targeting

8. Endocytosis

9. Endosomal Escape

10. Release of the siRNA From the Polyplexes

11. mRNA Degradation and Protein Shutdown

12. Nanotoxicity

13. Conclusions

Acknowledgment

Abbreviations

19: Polymeric Nanobiomaterials for Tumor Targeting

Abstract

1. Introduction

2. Natural Polymeric Nanobiomaterials Used for Tumor Targeting

3. Synthetic Polymeric Nanobiomaterials Used for Tumor Targeting

4. Patents of Polymeric Nanobiomaterials for Tumor Targeting

5. Current Status and Commercial Aspects

6. Conclusions

20: Alginate Containing Nanoarchitectonics for Improved Cancer Therapy

Abstract

1. Introduction

2. Advantages of the Use of Alginate Nanocarriers for the Treatment of Cancer

3. Disadvantages of the Use of Alginate Nanocarriers for the Treatment of Cancer

4. Physical and Chemical Properties of Alginate

5. Nanotechnology for Cancer Treatment

6. Alginate Nanocarriers

7. Preparation of Alginate Nanoparticles

8. Alginate Nanocarriers for Controlled Drug Delivery

9. Alginate Nanocarriers for the Treatment of Various Cancers

10. Future Prospects

11. Conclusions

21: Multifunctional Magnetic Nanostructures for Cancer Hyperthermia Therapy

Abstract

1. Introduction

2. An Overview of Cancer Treatments

3. Hyperthermia Treatment for Cancer

4. Theory of Magnetic Fluid Hyperthermia

5. Literature Survey on MNPs Used for Hyperthermia

6. Surface Coating on Magnetic Nanoparticles for Hyperthermia

7. Biocompatibility Issue of Magnetic Nanoparticles for Hyperthermia

8. In Vitro and In Vivo Hyperthermia

9. In Vivo Hyperthermia by Using Magnetic Nanoparticles: Challenges, Possibilities, and Outcomes

10. Conclusions and Future Perspectives

Acknowledgment

22: Advances in Lasers and Nanoparticles in Treatment and Targeting of Epithelial Originated Cancers

Abstract

1. Introduction

2. Cancer

3. Principles of Nanotechnology

4. Principles of Lasers

5. Combination of Lasers and Nanoparticles for Treatment of Cancers With Epithelial Origin

6. Discussion

7. Conclusions

23: Gold Nanoparticles: Their Properties and Role as Therapeutic Anticancer Agents

Abstract

1. Introduction

2. Cancer and Its Types

3. Properties of AuNPs

4. Synthesis of AuNPs

5. Bioapplications

6. Drawbacks of AuNPs

7. Future Aspects

8. Conclusions

24: Iron Oxide Nanoparticles for Cancer Diagnosis and Therapy

Abstract

1. Introduction

2. Basic Requirements for Biomedical Applications

3. Synthesis of Iron Oxide Nanoparticles

4. MNP Surface Modification

5. Application of Therapeutic Iron Oxide Nanoparticles in Cancer Diagnosis and Treatment

6. Future Prospects for Nanotechnology in Cancer Medicine

25: Nanoparticle and Targeted Systems for Colon Cancer Therapy

Abstract

1. Overview

2. Cancer Nanotechnology

3. Classes of Nanomaterials

4. Nanoparticle-Based Colon-Specific Drug Delivery

5. Nanotherapies for Colon Cancer

Abbreviations

26: Nanohybrid Stimuli-Responsive Microgels: A New Approach in Cancer Therapy

Abstract

1. Introduction

2. Microgels and Nanogels

3. Stimuli-Responsive Polymers

4. Synthesis of Microgels and Nanogels

5. Applications in Cancer Therapy

6. Conclusions

27: Multifunctional Magnetic Liposomes for Cancer Imaging and Therapeutic Applications

Abstract

1. Introduction

2. Chronological Developmental Stages of Cancer Therapeutics

3. Cancer Imaging—A Crucial Diagnosis Method

4. Overview of the Different Magnetic Nanostructures Used in Cancer Theragnostic Applications

5. Cancer Targeting

6. Magnetic Liposomes and Their Applications in Nanomedicines

7. Stimuli-Responsive Release of Anticancer Agents From Magnetic Liposomes

8. Magnetic Liposomes for Overcoming Multidrug Resistance in Tumors

9. Biocompatibility and Toxicity Issues

10. Current Status and Future Prospects

11. Challenges Encountered

12. Conclusions

Acknowledgments

28: The Chemotherapeutic Potential of Gold Nanoparticles Against Human Carcinomas: A Review

Abstract

1. Introduction

2. Nanoparticles

3. Green Synthesis

4. M. oleifera Leaves and Flowers

5. Gold Nanoparticles

6. Gold Nanoparticles in Chemotherapy

7. Potential Targets for Chemotherapy

8. Conclusions and Future Prospects

Acknowledgments

29: Nanotherapeutic Platforms for Cancer Treatment: From Preclinical Development to Clinical Application

Abstract

1. Cancer

2. Nanocarriers

3. Mechanisms of Targeted Delivery of Nanocarriers

4. Nanocarriers for Cancer Therapy in Clinical Development

5. Ligand-Based Active Targeting in Preclinical Development

6. Concluding Remarks and Future Perspectives

30: The Scientometric Overview in Cancer Targeting

Abstract

1. Overview

2. The Nanoparticle Anticancer Nanobiomaterials

3. The Other Anticancer Nanobiomaterials

4. Conclusions

Index

Copyright

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List of Contributors

J. Abraham,     VIT University, School of Biosciences and Technology, Microbial Biotechnology Laboratory, Vellore, Tamil Nadu, India

B.A. Aderibigbe,     Department of Chemistry, University of Fort Hare, Alice, South Africa

H. Afshar,     Mechanical Engineering Department, East Tehran Branch, Islamic Azad University, Tehran, Iran

V. Aina,     Department of Chemistry and NIS Interdepartmental Centre, University of Turin, Turin, Italy

N. Alam,     Formulation & Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India

S. Banerjee,     Implants, Devices & Drug Delivery Systems (ID3S) Laboratory, Centre for Bio-design (CBD), Translational Health Science & Technology Institute (THSTI), Faridabad, Haryana, India

A. Bhatt,     Pharmaceutics Research Laboratory, Department of Pharmaceutics, Adina Institute of Pharmaceutical Sciences, Sagar, Madhya Pradesh, India

R. Bohara,     Center for Interdisciplinary Research, D. Y. Patil University, Kolhapur, Maharashtra, India

M.L. Bruschi,     State University of Maringá, Department of Pharmacy, Laboratory of Research and Development of Drug Delivery Systems, Maringá, Brazil

D. Casotti,     Department of Physics and Earth Sciences, University of Ferrara, Ferrara, Italy

G. Cerrato,     Department of Chemistry and NIS Interdepartmental Centre, University of Turin, Turin, Italy

D. Chen

College of Materials and Environmental Engineering, Hangzhou Dianzi University, Hangzhou

Key Lab of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, CAS, Fuzhou, P.R. China

A.A. Chuturgoon,     Discipline of Medical Biochemistry and Chemical Pathology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa

G. Cruciani,     Department of Physics and Earth Sciences, University of Ferrara, Ferrara, Italy

A. D’Souza,     Department of Bioscience and Bioengineering, Indian Institute of Technology-Bombay (IIT-B), Mumbai, India

C. Dalwadi,     Department of Pharmaceutics and Pharmaceutical Technology, Ramanbhai Patel College of Pharmacy, Charotar University of Science & Technology (CHARUSAT), Changa, Gujarat, India

M. Ding,     College of Materials and Environmental Engineering, Hangzhou Dianzi University, Hangzhou, P.R. China

R.D. Dubey,     Formulation & Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India

S.P. Egusquiaguirre

NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU)

Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain

B. Evrard,     Laboratory of Pharmaceutical Technology and Biopharmacy—CIRM, University of Liege, Liege, Belgium

R. Fekrazad

Laser Research Center in Medical Sciences, AJA University of Medical Sciences

International Network For Photo Medicine And Photo Dynamic Therapy (INPMPDT), Universal Scientific Education and Research Network (USERN), Tehran, Iran

A. Frère,     Laboratory of Pharmaceutical Technology and Biopharmacy—CIRM, University of Liege, Liege, Belgium

M. Ghassemi,     Mechanical Engineering Department, K.N. Toosi University of Technology, Tehran, Iran

E. Ghedini,     Department of Molecular Science and Nanosystems, Ca’ Foscari University Venice, INSTM Consortium Venice RU, Mestre, Italy

T.K. Giri,     NSHM College of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata Group of Institutions, Kolkata, West Bengal, India

N. Giribabu,     Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

M. Gogoi,     Department of Biomedical Engineering, North-Eastern Hill University, Shillong, Meghalaya, India

P.N. Gupta,     Formulation & Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India

E. Gurnany,     Pharmaceutics Research Laboratory, Department of Pharmaceutics, Adina Institute of Pharmaceutical Sciences, Sagar, Madhya Pradesh, India

M.R. Habibi,     Research Institute of Petroleum Industry, Tehran, Iran

M. Hamidi,     Zanjan Pharmaceutical Nanotechnology Research Center (ZPNRC) and Department of Pharmaceutical Nanotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran

L.-Y. Hao,     School of Materials Science and Engineering, Jinling Institute of Technology, Nanjing, P.R. China

R.M. Hernández

NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU)

Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain

X.-H. Hu,     School of Materials Science and Engineering, Jinling Institute of Technology, Nanjing, P.R. China

M. Igartua

NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU)

Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain

A. Jain,     Pharmaceutics Research Laboratory, Department of Pharmaceutics, Adina Institute of Pharmaceutical Sciences, Sagar

A. Jain,     Pharmaceutics Research Laboratory, Department of Pharmaceutics, Ravishankar College of Pharmacy, Bhopal

R. Jain,     Pharmaceutics Research Laboratory, Department of Pharmaceutics, Adina Institute of Pharmaceutical Sciences, Sagar, Madhya Pradesh, India

M. Kaur,     University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India

R.K. Kesrevani,     School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, India

O. Konur,     Yildirim Beyazit University, Faculty of Engineering and Natural Sciences, Department of Materials Engineering, Ankara, Turkey

M.R. Koshkaki,     Biomaterials and Tissue Engineering Research Group, Breast Cancer Research Center (BCRC), Academic Center for Education, Culture and Research (ACECR), Tehran, Iran

N. Kumar,     Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India

L. Kumari,     Department of Pharmaceutics, Gupta College of Technological Sciences, Asansol, West Bengal, India

Y. Luengo,     Department of Biomaterials and Bioinspired Material, Materials Science Institute of Madrid (ICMM)/CSIC, Madrid, Spain

S. Maiti,     Department of Pharmaceutics, Gupta College of Technological Sciences, Asansol, West Bengal, India

K. Majidzadeh-A

Biomaterials and Tissue Engineering Research Group, Breast Cancer Research Center (BCRC), Academic Center for Education, Culture and Research (ACECR)

Tasnim Biotechnology Research Center, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran

A. Maleki,     Zanjan Pharmaceutical Nanotechnology Research Center (ZPNRC) and Department of Pharmaceutical Nanotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran

M. Marciello,     Department of Biomaterials and Bioinspired Material, Materials Science Institute of Madrid (ICMM)/CSIC, Madrid, Spain

G. Martra,     Department of Chemistry and NIS Interdepartmental Centre, University of Turin, Turin, Italy

A. Modi,     Pharmaceutics Research Laboratory, Department of Pharmaceutics, Adina Institute of Pharmaceutical Sciences, Sagar, Madhya Pradesh, India

M.P. Morales,     Department of Biomaterials and Bioinspired Material, Materials Science Institute of Madrid (ICMM)/CSIC, Madrid, Spain

D. Mottet,     Protein Signalisation and Interaction—GIGA, University of Liege, Liege, Belgium

H.E. Mukaya,     Department of Applied Chemical Technology, University of Johannesburg, Doornfontein Campus, Johannesburg, South Africa

V. Nichele,     Department of Molecular Science and Nanosystems, Ca’ Foscari University Venice, INSTM Consortium Venice RU, Mestre, Italy

M. Nikhalat,     Laser Research Center of Dentistry, Tehran University of Medical Sciences, Tehran, Iran

H. Nokhbatolfoghahaei,     Laser Research Center of Dentistry, Tehran University of Medical Sciences, Tehran, Iran

S.V. Otari,     Center for Interdisciplinary Research, D. Y. Patil University, Kolhapur, Maharashtra, India

P.M. Outuki,     State University of Maringá, Department of Pharmacy, Laboratory of Research and Development of Drug Delivery Systems, Maringá, Brazil

B.-D. Park,     Department of Wood Science and Technology, Kyungpook National University, Daegu, Republic of Korea

G. Patel,     Department of Pharmaceutics and Pharmaceutical Technology, Ramanbhai Patel College of Pharmacy, Charotar University of Science & Technology (CHARUSAT), Changa, Gujarat, India

S. Patra,     Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India

S.H. Pawar,     Center for Interdisciplinary Research, D. Y. Patil University, Kolhapur, Maharashtra, India

J.L. Pedraz

NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU)

Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain

A. Phulukdaree,     Discipline of Medical Biochemistry and Chemical Pathology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa

G. Piel,     Laboratory of Pharmaceutical Technology and Biopharmacy—CIRM, University of Liege, Liege, Belgium

J. Pillai,     Implants, Devices & Drug Delivery Systems (ID3S) Laboratory, Centre for Bio-design (CBD), Translational Health Science & Technology Institute (THSTI), Faridabad, Haryana, India

F. Pinna,     Department of Molecular Science and Nanosystems, Ca’ Foscari University Venice, INSTM Consortium Venice RU, Mestre, Italy

P.V. Rao,     Faculty of Agro Based Industry, University Malaysia Kelantan, Campus Jeli, Kelantan, Malaysia

N. Salleh,     Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

A. Saneja,     Formulation & Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India

A. Sarwal,     University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India

A. Seyfoori

Biomaterials and Tissue Engineering Research Group, Breast Cancer Research Center (BCRC), Academic Center for Education, Culture and Research (ACECR)

School of Metallurgy and Materials Engineering, College of Engineering, University of Tehran, Tehran, Iran

A. Shahidian,     Mechanical Engineering Department, K.N. Toosi University of Technology, Tehran, Iran

A. Sharma,     Department of Pharmaceutics, Chitkara College of Pharmacy, Chitkara University, Patiala, Punjab, India

A.K. Sharma,     Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences & Research, New Delhi, India

S. Sharma,     University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India

R. Shegokar,     Freie Universität Berlin, Institute of Pharmacy, Department Pharmaceutics, Biopharmaceutics, and NutriCosmetics, Berlin, Germany

M. Signoretto,     Department of Molecular Science and Nanosystems, Ca’ Foscari University Venice, INSTM Consortium Venice RU, Mestre, Italy

Silki,     University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India

N. Singh,     VIT University, School of Biosciences and Technology, Microbial Biotechnology Laboratory, Vellore, Tamil Nadu, India

I. Singh,     Department of Pharmaceutics, Chitkara College of Pharmacy, Chitkara University, Patiala, Punjab, India

V.R. Sinha,     University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India

N.D. Thorat

Department of Physics & Energy, University of Limerick; Materials & Surface Science Institute, University of Limerick, Limerick, Ireland

Center for Interdisciplinary Research, D. Y. Patil University, Kolhapur, Maharashtra, India

C. Tiloke,     Discipline of Medical Biochemistry and Chemical Pathology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa

S.A.M. Tofail,     Department of Physics & Energy, University of Limerick; Materials & Surface Science Institute, University of Limerick, Limerick, Ireland

M. Villa Nova,     State University of Maringá, Department of Pharmacy, Laboratory of Research and Development of Drug Delivery Systems, Maringá, Brazil

H.M. Yadav,     Department of Materials Science and Engineering, University of Seoul, Seoul, South Korea

X.-J. Zhang,     School of Materials Science and Engineering, Jinling Institute of Technology, Nanjing, P.R. China

Preface

Science and engineering have made enormous progress in many fields that have significantly improved our quality of life. However, as the pace of life is rapidly changing, the progress of scientific research must also reach an incredible speed in order to keep up with the emerging needs of individuals in terms of health and well-being. The nanotechnology revolution has been widely discussed in both the scientific and popular press, and a consensus has emerged that nanotechnology and nanoscience will offer important advances for the design of novel solutions to many diseases and health-threatening conditions in the modern age. This book was motivated by the great interest of the current scientific community regarding recent advances and applications of nanotechnology in medical practice, especially in challenging and delicate fields, such as cancer therapy. Moreover, there is a large amount of available research material that could offer overwhelming perspectives in therapy and diagnosis needed to reach a wider audience.

The most significant novel aspects offered by this work are represented by its focus on the architecture of nanosized materials, known as nanoarchitectonics, which represents a new, complex, and emerging field situated at the intersection of engineering, physics, chemistry, and materials science. This amazing field has the potential to offer cutting-edge solutions to various difficult-to-achieve therapies, by facilitating the precise and tailored control of morphology, physicochemical properties, and even the biological effects of nanometer-sized drugs.

Although primarily addressed to the scientific community, this book offers valuable and accessible information for a wide range of readers interested in the current technological progress with direct relevance to the biomedical field. Current medical applications and diseases with broad scientific interest, such as cancer, are covered, and the readers will find the most innovative and relevant aspects of nanotechnology in medicine.

All the chapters within the book were prepared by outstanding researchers and experts, who have made important contributions in a particular field within the broad domain of nanotechnology and drug delivery. The chapters are clearly written and well illustrated to increase the readers’ interest.

I truly believe that the work presented in this book will increase knowledge and awareness regarding the applications of the new field of nanoarchitectonics in drug delivery and design of novel therapies for difficult to treat diseases.

Michael R. Hamblin

Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, United States

Department of Dermatology, Harvard Medical School, Boston, MA, United States

Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, United States

Part 1

Smart Delivery

1: Therapeutic Nanostructures: Application of Mechanical Engineering in Drug Delivery

2: Nanoarchitectured Biomaterials: Present Status and Future Prospects in Drug Delivery

3: Smart Nanopolysaccharides for the Delivery of Bioactives

4: Drug-Delivery Applications of Cellulose Nanofibrils

5: Nanoarchitectured Polysaccharide-Based Drug Carrier for Ocular Therapeutics

6: Current Polyesteric Systems for Advanced Drug Delivery

7: Nanobiomaterials Architectured for Improved Delivery of Antimalaria Drugs

8: Formulation of Innovative Hybrid Chitosan/TiO2- and Chitosan/SiO2-Based Drug-Delivery Systems

9: Lanthanide Ions Doped Upconversion Nanomaterials: Synthesis, Surface Engineering, and Application in Drug Delivery

10: Nanocomposite Drug Carriers

11: Lipid Nanoparticle Formulations for Enhanced Antituberculosis Therapy

12: Relevant Aspects on Peptide Delivery from Nanostructured Therapeutic Systems

13: Nanoarchitectured Mesoporous Silica-Based Drug-Delivery Systems: Toward Perfect Nanomedicine

14: Recent Advances in Self-Emulsifying Drug-Delivery Systems for Oral Delivery of Cancer Chemotherapeutics

15: Scientometric Overview in Nanobiodrugs

1

Therapeutic Nanostructures: Application of Mechanical Engineering in Drug Delivery

A. Shahidian*

H. Afshar**

M.R. Habibi†

M. Ghassemi*

*    Mechanical Engineering Department, K.N. Toosi University of Technology, Tehran, Iran

**    Mechanical Engineering Department, East Tehran Branch, Islamic Azad University, Tehran, Iran

†    Research Institute of Petroleum Industry, Tehran, Iran

Abstract

The purpose of this chapter is to discuss the application of lasers and metal nanoparticles for the treatment of cancers with epithelial origin. The combination of laser therapy and nanoparticles in cancer treatment includes four major sections: (1) Cancer (2) Principals of nanotechnology (3) Principles of laser (4) Combination of laser and nanoparticles for treatment of cancers with epithelial origin. Disadvantages of lasers and nanoparticles combined therapy include high cost and difficulty of finding identical particles. Besides, it requires complicated and advanced technology, which may not be easily obtained. It can be concluded that laser and nanoparticles together are novel classes of cancer therapy and diagnosis. More studies should be done to rule out the most effective nanoparticles and laser wavelength. Also, more animal studies and clinical trials need to be completed, as there has always been a lack of perfect studies in the field. These methods and mechanisms can be used as a treatment modality to aid in the cure of cancers in the future.

Keywords

cancer therapy

laser therapy

Au nanoparticle

Ag nanoparticle

combination of Au/Ag

metal nanoparticle

epithelial cell

Nanotechnology is a novel idea that uses the existing knowledge and technology to create new material and systems. One of the goals of most scientists and engineers is to reach new approaches to solve human problems using nanotechnology, especially in medicine. Drug delivery using nanotechnology is a novel idea in medicine and is still in its primary stages. Delivery of drug by nanosystems reduces side effects in live tissues when compared to other methods. For instance, pharmaceutical researchers are using nanoparticles to reduce toxicity and its side effects. Engineers are trying to design nanosystems for carrying and delivering the drug to the desired place.

The purpose of the current chapter is to present the behavior of a nanoparticle as a drug carrier inside a live body. The goal is to solve the governing equations, Navier–Stokes, energy, and Maxwell equations, to simulate the fluid flow and heat transfer in order to find an efficient way for drug delivery with minimum side effects.

In the proposed chapter, after providing the readers with a brief introduction to drug delivery, we shall discuss the mechanical engineering application in advanced drug delivery systems based on nanoparticles.

1. Introduction

1.1. Drug Delivery Definition

Drug delivery system (DDS) is defined as approaches, formulations, technologies, and devices that are used for transporting a pharmaceutical compound in the body as needed so that its desired therapeutic effect can be safely achieved. In this system, various devices and formulations of drugs are used. The pharmaceutical or diagnostic nanoparticles play a significant role in improving the drug delivery.

In fact, by the use of drug delivery technologies, the drug release profile is modified; product efficiency and safety as well as patient convenience and compliance are improved.

The diffusion, degradation, swelling, and affinity-based mechanisms are symptoms of drug release (Wang and Von Recum, 2011). Based on the disease, the effect desired, and the product available, there are different anatomical routes by which drugs may be introduced into the human body. Among the most common routes of administration are the preferred noninvasive peroral (through the mouth), topical (skin), transmucosal (nasal, buccal/sublingual, vaginal, ocular, and rectal), and inhalation routes. Moreover, gene therapy can be suitably included in the basic and broad definition of a drug delivery system. Novel delivery methods may be used in case gene vectors need to be introduced into the human body. By the use of these routes, however, many medications, such as antibody, peptide and protein, and vaccine-and-gene-based drugs are difficult to deliver. The main factors that make delivery inefficient are molecular size and charge issues. Studies reported that these parameters are susceptible to enzymatic degradation or they are difficult to get efficiently absorbed into the systemic circulation to be efficient for therapy. To overcome these issues, therapy based on the utilization of injection or nanoneedle arrays have emerged, in order to deliver many proteins and peptide drugs. Novel approaches in drug delivery are based on the development of targeted delivery and controlled release of the drugs over a period of time. However, the system intended for the delivery must fill in some characteristics, such as to be able to avoid the defense mechanisms of the host and circulate to its designed site of action (Bertrand and Leroux, 2012). Samples of sustained release formulations include drug loaded biodegradable microspheres, liposomes, and drug polymer conjugates.

1.2. Nanotechnology

Again, nanotechnology is a novel idea that uses the existing knowledge and technology to create new material and systems. On the other hand, it involves the study of the control of matter on an atomic and molecular scale. This molecular level investigation is at a range usually below 100 nm. Although the initial properties of nanomaterials were studied for their physical, mechanical, electrical, magnetic, chemical, and biological applications, recently, attention has been geared toward its pharmaceutical application, especially in the area of drug delivery.

One of the goals of most scientists and engineers is to reach new approaches to solve human problems using nanotechnology, especially in medicine. Several useful nanotechnological applications have been identified in cancer biology, including technologies for the early detection of tumors and cancer biomarkers, and the development of treatment approaches that are impossible to achieve using conventional technologies (Stolnik et al., 2012).

Nanotechnology has finally and firmly entered the realm of drug delivery. Performances of intelligent drug delivery systems are continuously improved with the purpose of maximizing therapeutic activity and minimizing undesirable side effects.

1.3. Applying Nanotechnology to Drug Delivery Systems

There are different approaches to classification of nanotechnology application in drug delivery. But it must be considered that applying nantotechnology for drug delivery must be proper for human health standards. Some of the important nanocarriers and nanoparticles used in drug delivery are described as follows.

1.3.1. Nanocarrier and Application

The proper classification for nanocarrier in drug delivery is based on three different categories, using various material, shape, or different medical application. Nanoparticles (NPs) used as drug delivery vehicles, consist of different biological substances, such as gelatin and phospholipids for liposomes and albumin, to chemical substances, such as various polymers and solid metal-containing NPs. Polymer–drug conjugates, which have high size variation, are normally not considered as NPs. However, polymer–drug conjugates with sizes under 100 nm are included in these nanodelivery systems. These nanodelivery systems can be designed to have drugs absorbed or conjugated onto the particle surface, encapsulated inside the polymer/lipid, or dissolved within the particle matrix (Kingsley et al., 2006). Several main nanocarriers are described in Table 1.1.

Table 1.1

Nanocarrier With Various Materials

1.3.2. Nanocarrier With Various Shape and Size

To achieve effective drug delivery, nanocarriers must have suitable circulation time to reaching their target. Some important key factors that impact the efficiency of drug delivery systems are size, shape, and surface characteristics of nanocarriers. Particle size plays a key role in particle functions, such as degradation, vascular dynamics, targeting, and clearance and uptake mechanisms (Champion et al., 2007). Particles have been shown to have different velocities, diffusion characteristics, and adhesion properties, depending on their size (Shinde Patil et al., 2001), resulting in different uptake efficiencies (Nel et al., 2009), (Goula et al., 1998). The size of nanodrugs should be large enough to prevent rapid leakage in blood capillaries, but at the same time, small enough to escape the capture of macrophages in the reticuloendothelial system, such as the liver and spleen. Some of the main outcomes reported in these studies are that the size limits for internalization of NPs through endocytosis are clearly cell dependent; particles less than 200 nm in size will mainly follow endocytic pathways; particles above this size can be either engulfed through endocytosis or not internalized at all, and microsized particles have to be internalized by phagocytic pathways (Prokop and Davidson, 2008). Interestingly, in the case of spherical Au NPs, it was found that the maximum uptake occurred with Au NPs 50 nm in diameter (Chithrani et al., 2006). It was reported that a diameter of 50 nm is the optimal size to achieve the most efficient endocytosis of MNSs. Also, the shape of particles can have an intriguing effect on particle functions, especially in biological processes, including internalization, transport through the blood vessels, and targeting diseased sites (Champion and Mitragotri, 2006; Geng et al., 2007). Varying toxicities of materials having identical chemical composition (silica) but different shapes (nanowire vs NP) were also reported (Adili et al., 2008). Recent advances with particular focus on the importance of particle shape are reviewed elsewhere (Doshi and Mitragotri, 2009).

Another important factor is the surface characteristics of NPs. This can also determine their lifespan during circulation in the blood stream. One of the major breakthroughs in this area was the finding that particles coated with hydrophilic polymer molecules, such as PEG, can resist serum protein adsorption, prolonging the systemic circulation of the particle (Moghimi et al., 2001). Since then, numerous variations of PEG and other hydrophilic polymers have been tested for improved circulation.

The surface charge on the particle also affects other functions, such as internalization by macrophages. Positively charged particles have been shown to exhibit higher internalization by macrophages and dendritic cells compared with neutral or negatively charged particles, although surface charge effect could also be cell-type dependent (Chung et al., 2007). The effects of particle size and surface chemistry on particle function have been reviewed elsewhere (Doshi and Mitragotri, 2009; Stolnik et al., 2012).

1.3.3. Targeting Strategies

Efficient design of drug nanocarriers rely mainly on two properties: (1) drugs should be able to reach the desired tissue, and (2) drugs should only interfere with target tissues (ie, tumor cells) and cells without harmful effects to healthy tissue (Shinde Patil et al., 2001). So, two strategies are used: passive and active targeting of drugs (Sinha et al., 2006).

Through leaky vascularization, nanoparticles (NPs) can be passively extravasated due to the enhanced permeability and retention effect, which allows them to be accumulated at the tumor region. In this case, drugs can possibly be freed in the extracellular matrix and then spread through the tissue. The therapeutic efficacy of drugs can be enhanced by active targeting via an increase in the growth and cellular uptake of NPs. NPs can possibly be engineered so that ligands binding to the receptors of endothelial cell surface can be incorporated.

1.3.4. Passive Targeting

Passive targeting refers to the characteristics of tumor vessels that enable the accumulation of nanodrugs in tumor tissues. The morphology of tumors allows molecules with a dimension under 400 nm to reach the tumor region by the phenomenon entitled leaky vascularization (Sinha et al., 2006; Smith et al., 2008). The first nanoscale-based technology refers to liposomes developed to ensure passive targeting of drugs. Recently, many types of liposomes have been specifically tailored to ensure best drug encapsulation, targeting, and controlled release at desired sites. Recent approaches are based on an additional polymeric coating aiming to protect the liposome drug-delivery nanosytem from immune destruction (Kubik et al., 2005; Pelicano et al., 2006; Yatvin et al., 1980).

Although important progress has been made regarding passive targeting, many limitations remain, mainly regarding the presence of an universal targeting cell within a tumor, which is not feasible because some drugs cannot diffuse efficiently, and the control of drug release is difficult to achieve (Jain, 1994).

1.3.5. Active Targeting

Opposite to passive targeting, active targeting has the advantage of utilizing specialized targeting molecules and ligands, such as: antibodies, peptides, aptamers, or small molecules that only bind to specific receptors on the cell surface (Sudimack and Lee, 2000; Arap et al., 1998; Leamon and Reddy, 2004). These ligands are usually linked to the surface of the nanocarriers by conjugation chemistry. Ligand-containing nanocarriers are able to recognize and attach to target cells through ligand–receptor interactions. Some parameters are very important in efficient tumor targeting, for example, receptors should be highly expressed on tumor cells, but not on normal cells in order to achieve high specificity; and the receptors should not be shed into the blood circulation. The most important aspect to ensure an efficient targeting is the correct application of targeting molecules and the selection of the most appropriate delivery system (Farokhzad and Langer, 2009).

2. Application of Electromagnetism in Drug Delivery

Nanotechnology and the science of nanoparticles is revolutionary to humankind, especially in the medical field. Since many years ago, the magnet has been used for industrial and engineering applications. When we combine the nanoparticle and its appreciable properties with the magnetic field, we can produce intelligent particles that can be guided remotely by changing magnet gradient and intensity. In biological application, magnetic nanoparticles should be compatible with in vivo environment. Until today, iron oxide for chemical compatibility as well as easy production and adaptation has attracted the most attention in the medical field (Berthier and Silberzan, 2006).

2.1. Properties of Magnetic Nanoparticles

The magnetic properties of materials are the result of the magnetic moment of electrons. Each electron in an atom has a magnetic moment, which arises from two sources: one related to the orbital motion of electrons around the nucleus, and another related to the rotation around the axis that is called the spine. Thus, each electron in an atom with orbital and spin moments can be permanently acted upon like a tiny magnet. Magnetization is a base of classification for magnetic materials. Accordingly, the materials classify into three groups: ferromagnetic, paramagnetic, and diamagnetic. Magnetization of diamagnetic materials is negative and very low. The resultant magnetic dipole moment in these materials is zero. All gases (except oxygen), water, silver, gold, copper, diamond, graphite, bismuth, and many organic compounds are diamagnetic materials. Induced magnetic dipole in these materials is opposite of the external magnetic field and with elimination of the external field, these induced magnets cancel (Carpenter, 2001).

In paramagnetic materials, bipolar magnet orientation is not regular. As a result, these materials are not magnetic. If the material is placed in a magnetic field, the magnetic field lines regulate quickly to the external magnetic field. By removing the magnetic field, the magnetic bipolar quickly return to their previous status. Magnetization of these materials is positive and about 10−6–10−1 (Berthier and Silberzan, 2006). Manganese, platinum, aluminum, and alkali metals are paramagnetic materials.

Ferromagnetic materials are like paramagnetic materials but they have a set of dipoles with the same direction. Magnetic nanoparticles used in medical applications belong to the paramagnetic materials. Also, particle coating and surfactant are the main factors in magnetic nanoparticles. A proper coating can prevent oxidation and being swallowed by white cells. Polysaccharide coatings like dextran and chitosan are widely used in the biological field. Hydrophilic surface coating results in a stable and uniform distribution of particles in the water and prevents unwanted ties and digestion of cells. The residence time of particles in the body depends on particle size, particle charge, hydrophilic surface, and intensity of magnetic field. These parameters are related to each other and measuring the effect of each individual one is a challenge in research (Owens and Peppas, 2006).

Novel physical, mechanical, and chemical properties can be observed when the size of materials approaches the nanoscale. The physical properties include optical, magnetic, and electrical properties. It has been found that magnetic nanoparticles behave differently from other larger ones, especially in magnetization. One of the most important properties that should be considered in biomedical application is residual magnet in materials. It should be cancelled when the external magnet is off (Bonnemain, 1998).

2.2. Biological Application

When these materials are used in the biological field, special restrictions should be considered and all possible reactions with the biological materials should be predicted. Magnetic properties should be maintained for a specific time during the test. Some applications can be classified as follows:

2.2.1. Magnetic Separation

Magnetic separation is used for clinical application, such as in the separation of proteins, toxemic materials, DNA, and bacteria and viruses. This is also used for real time detecting of viruses. The most important stage in this field is the labeling of molecules with magnetic materials by a reliable connection. Magnetic beads from iron oxide are typically used for biological separation. The main properties of iron oxide are super paramagnetic properties (Meza, 1997).

2.2.2. Drug and Gene Delivery

Effective drug delivery can greatly improve the process of treatment and reduce side effects. In this method, while the amount of drug decreases, the concentration of the drug in the target area increases. Protecting the drug before its gets to the target area is one of the most important factors, because after releasing the drug in the blood stream, white cells detect the drug and swallow them in a short time. An ideal nanoparticle for drug delivery should have the potential to combine with a relatively high-weight drug and disperse uniformly in the blood stream (Shultz et al., 2007).

2.2.3. Hyperthermia

Also, while chemotherapy is one of most effective methods for cancerous tissues, many of the other healthy cells are destroyed in the process. So the conventional thermotherapy has many side effects. In hyperthermia treatment, after delivering the drug to the target area, an AC magnetic field is used to generate controllable energy and increase temperature. Heat transfer in this process is a balance between blood flow, heat generation, and tissue porosity and conductivity (Sellmyer and Skomski, 2006).

2.2.4. MRI Imaging

Magnetic Resonance Imaging (MRI) is considered a great help in the diagnoses of many diseases. The advantages of this imaging are high contrast in soft tissue, proper resolution, and sufficient penetration depth for noninvasive diagnosis. In fact, in MRI imaging magnetization of protons is measured when exposed to the magnetic field with radio frequency (Corot, 2006).

2.3. Governing Equations

Three sets of equations can be observed in the biology field. The first one is base fluid that in most conditions is a non-Newtonian fluid. The second one is solid particles that include the drug, magnetic nanoparticles, surfactant, and some chemical materials for bonding drug to nanoparticles. The third set of equations involves the magnetic and electric fields and their interaction with the magnetic nanoparticles. This field controls the motion of particles in base fluids.

2.3.1. Biofluid Equations

Governing equations for biofluids include the Navier–stokes equations and thermophysical equations for parameters like density, viscosity, and diffusion of base biofluid. Navier–Stokes equations in Cartesian coordinates for two-dimensional problems are according to Eqs. 1.1–1.3 (Berthier and Silberzan, 2006).

Continuity equation

(1.1)

X component momentum

(1.2)

Y component momentum

(1.3)

Energy equation:

(1.4)

The shear stress τ are:

(1.5)

In Eq. 1.10, the shear stress tensor is given by:

(1.6)

The shear rate is defined as:

(1.7)

For blood viscosity, Eq. 1.7 can be used. It should be noted that many models are introduced for blood viscosity and each of them has some advantages and some disadvantages.

(1.8)

where values of m and n are 0.012 and 0.8, respectively (Kleinstreuer, 2003).

2.3.2. Source Terms

Interaction between solid phase and magnetic field with biofluid is modeled via source terms in Navier–Stokes and energy equations. These source terms for FHD (Ferro hydrodynamics) problems are equal to Eqs. 1.9–1.11 (Berthier and Silberzan, 2006).

(1.9)

(1.10)

(1.11)

2.3.3. Solid Phase Equations

Each magnetic nanoparticle is absorbed by the external magnetic field. This absorption can be modeled by Eq. 1.12. In this equation, H, μ0, and χ are external magnetic field, magnetic permeability of vacuum, and magnetic susceptibility of the particles, respectively. It should be noted that P refers to particle (Hautot, 2003).

(1.12)

For n particles, magnetic force is equal to:

(1.13)

(1.14)

Fx and Fy are the effect of particles aggregation near magnet on the blood flow.

(1.15)

(1.16)

Volume concentration is defined as:

(1.17)

Nondimensional concentration can be defined as:

(1.18)

C0 is initial concentration that should be set before the test or numerical simulation.

Particles concentration is calculated using the following equation:

(1.19)

VP is particle velocity that is calculated by writing the Newton equation for each particle in uniform motion as the following:

(1.20)

(1.21)

Vf is blood flow velocity and DP is particle diameter. Diffusion coefficient in Eq. 1.12 is calculated from the Einstein equation (Berthier and Silberzan, 2006):

(1.22)

kB is a Boltzmann constant and T is temperature.

2.3.4. Magnetic Field Equations

In general cases, Maxwell equations express the magnetic behavior of materials in steady and unsteady conditions (Fitzpatrick, 2008).

(1.23)

(1.24)

(1.25)

(1.26)

E is an electrical field and B is magnetic field. C is the speed of the light and J is the vector current density. With regard to these equations in steady conditions, magnetic induction in the external magnetic field is shown in the following equation:

(1.27)

μ0 is the permeability of free space. Magnetization (M) is given by:

(1.28)

In Eq. 1.28, χ is volumetric magnetic susceptibility (dimensionless).

2.4. Boundary Conditions

Boundary conditions depend on the problem geometry and interaction with biofluid. If a solid wall is considered for blood veins, we can use a simple no sleep condition for velocity everywhere on the vein wall. But if the interaction between the vein wall and blood is considered, we must use the FSI (Fluid Solid Interaction) model. Other boundary conditions include mass flow rate, pressure, velocity, and gradient of these parameters. It should be noted that for porous media problems, normal velocity to the wall should be considered (Patankar, 1980).

2.5. Solution of Governing Equations

Due to nonlinear PDE equations in biofluid and magnetic field, an analytical solution is not expected unless for simple problems. However, for tracking nanoparticles in biofluid, two approaches exist: Eulerian and Lagrangian methods.

2.5.1. Eulerian Method

If Eulerian method is used for numerical simulation, the concentration equation should be solved with momentum and energy equations. Also, magnetic field should be solved initially for use in biofluid equations as a source term. If particle motion affects the external magnetic field, a simultaneous solution is necessary for Maxwell and Navier–Stokes equations. Fortunately, most nanoparticles never affect the external magnetic field and this condition reduces the complexity of equations (Habibi, 2012). Some researchers use two or three phase flows in numerical simulation for blood and particle, separately. Some researchers consider blood flow as a constant and solve the equation, but in fact, the nature of blood behavior is unsteady. Each numerical simulation needs a validation process and without this, we never rely on the results.

Magnetic nanoparticles concentration in unsteady biofluid is depicted in Fig. 1.1. In this case, Navier–Stokes, concentration, and Maxwell equations are solved. Rigid wall is considered as a boundary condition for the vein wall and velocity inlet for biofluid inlet (Habibi, 2012).

Figure 1.1   Dimensionless concentration for 200 nm magnetic nanoparticles in unsteady blood flow (Habibi, 2012).

The vein is modeled as a semichannel with 1 mm width and 20 mm length. The magnet is placed in the middle of the vein and nanoparticles are injected from the upper wall with 0.028 m/s velocity for 3 s.

2.5.2. Lagrangian Method

If we consider Lagrangian approaches for magnetic particles, we should track the path that each particle moves in blood.

Although in Lagrangian method the ordinary differential equation should be solved, the number of theses equations is equal to the number of particles. The most important forces are magnetic force and hydrodynamic force. If a more realistic solution is intended, other forces like weight, Brownian force, Basset force, lift force, acoustical force, and so on should be considered.

Sometimes a ferromagnetic wire or sphere is used in high uniform magnetic field for producing a better magnetic gradient field. Near this wire, a high gradient magnetic field is created. This wire is planted in the center of cancerous tissue to attract particles.

Diffusion of magnetic nanoparticles in a multisite injection process within a biological tissue during magnetic fluid hyperthermia is investigated numerically by Ali A. Golneshan and M. Lahonian. They use the lattice Boltzmann method for numerical simulation (Golneshan and Lahonian, 2011).

2.6. Experimental Results

In the biological field, less experimental research has been done and most of these experiments are applied for animals. An experimental test on the shape of particle aggregation was done by Balakin et al. (2012). The behavior of magnetic nanoparticles was investigated inside the microfluidic chip (Agiotis et al., 2016). This study shows that the electrical field makes the aggregation rotate in a static magnetic field.

3. Application of Ultrasonic Waves in Drug Delivery

Similar to audio sound, ultrasound refers to pressure waves at frequencies above 20,000 Hz that is higher than human hearing being transmitted through a medium such as air or water, and this is the same type of transmission of pressure waves. The ultrasonic waves are very physical in nature. The ultrasound can act physically upon biomolecules and cells because the ultrasonic waves are actual movement of molecules as the medium is compressed (at high-pressure) and expanded (at low-pressure). The ultrasonic waves, unlike visible light waves, are absorbed relatively little by water and different tissues. Therefore, ultrasound is visible in the body (eg, diagnostic ultrasound) and can be used to transmit energy into the targeted tissue in the body. This noninvasive and safe transmission of energy into the body is the important advantage of ultrasonic-activated drug delivery. The role that is played by the ultrasound (US) in delivering therapeutic agents, such as genetic material, proteins, and chemotherapeutic agents is very important.

Ultrasound has an effective role in the delivery of different pharmacological agents. Microbubbles as instances of cavitating gas bodies are the mediators, which concentrate the energy of pressure waves that are fairly noninteractive so that forces permeating cell membranes and dislocating the drug-carrying vesicles are produced. As a result, the delivery of genetic material, proteins, and smaller chemical agents is enormously enhanced by the presence of microbubbles. The ultrasound, especially in the presence of microbubbles, greatly enhances the delivery of genetic material. Gene uptake is even further increased through direct attachment of DNA to the microbubbles or to gas-containing liposomes. Researchers have studied gene delivery that is enhanced by ultrasound in different tissues, such as cardiac, vascular, skeletal muscle, tumor, and even fetal tissue. The most application of protein delivery that is enhanced by ultrasound has been found in transdermal delivery of insulin. The structure of the stratum corneum is reversibly disrupted by cavitation events so that the transportation of these large molecules can be allowed. The delivery of other hormones and small proteins could also be transdermal. The following two phenomena are caused by cavitation: disrupting the structure of the carrier vesicle and releasing the drug as well as making the membranes and capillaries of the cell more permeable to drugs. Of course, a need remains both for better understanding of the physics of cavitation of microbubbles and the influence/effect of such cavitation on vesicles that carry cells and the drug. Ultrasound can be used to release drugs from carriers, but it can also be used to induce bioeffects inside the body. The three physical mechanisms—heat generation, cavitation and radiation force—are used with ultrasound. These are elucidated in the following paragraphs.

3.1. Acoustic Radiation Force

Acoustic radiation forces occur at all pressures with the use of High Intensity Focused Ultrasound (HIFU), thereby causing the interacting material to displace in the direction of the ultrasound wave. This phenomenon occurs when a traveling ultrasound wave is absorbed or reflected by a particle, and the momentum associated with the wave produces primary ultrasound radiation force (USRF). This force causes the radiating sound wave to transfer to the particle. Radiation forces are proportional to the absorption coefficient of the tissue and the applied energy (Dayton et al., 2002).

In fluid mediums, the radiation force can produce a steady flow, also known as acoustic streaming, making it possible to direct fluids in a particular direction. Compressible objects, such as gas-filled microbubbles, experience much larger forces and are easier to displace (Frenkel, 2008). Therefore, acoustic radiation forces are commonly used to displace microbubbles. It is possible to push microbubbles that are circulating in the blood stream toward the vessel wall to increase uptake in that area. The movement of microbubbles to the vessel wall induces shear forces and can cause gaps in the endothelium of the vessel wall (Lum et al., 2006).

In addition to primary USRF, which acts in the direction of acoustic wave propagation, a secondary USRF acts between individual bubbles. The secondary USRF acts on the individual bubbles to attract each other, causing a greater concentration at the target.

(1.29)

(1.30)

(1.31)

(1.32)

(1.33)

(1.34)

(1.35)

(1.36)

Time averaged acoustic pressure in the inviscid fluid flow (p2) is represented by Eq. 1.37:

(1.37)

3.2. Heat Generation

The use of thermal elevation in local drug delivery goes back a long time and can be induced in multiple ways. For example, catheters (Ponce et al., 2007), microwaves, radiofrequency, infrared, or lasers. However, these methods are either invasive, only have superficial penetration depth, or inhomogeneous distribution of heat. The biggest advantage of using ultrasound to induce local heating is its noninvasive nature and deep penetration into the body. Another very important capability of ultrasound is that it can focus the heat very precisely, into a very small region in the body.

Elevation of temperature results from the absorption of ultrasound energy. This is directly proportional to the absorption coefficient to the tissue. It has a linear relation with the intensity of the ultrasound waves (Frenkel, 2008). Other properties of the treated tissue, like diffusion and convection inside of a vessel due to bloodstream, also influence the amount of heat generated (O’Neill et al., 2009).

Heating of tissue has different applications, depending on the temperature. With a great increase in temperature, up to 60°C, thermal ablation therapy is possible. In lower ranges of temperature elevations, the use of drug carriers is possible, for example, the low temperature sensitive liposomes (LTSL) that become sensitive to heat around 41°C (Ponce et al., 2007). This induces a locally enhanced concentration of the drug because they only release the drug at the target site. Heating inside the body also creates physiological changes in the tissue itself, such as an increase in blood flow and oxygenation. This process is very complex and not fully understood, and therefore is hard to predict (Kong et al., 2000).

The power carried per cross-section area of the beam, which typically has units of watts/cm², is used in order to measure the intensity of an ultrasonic beam, which is also called power density. In case a small-sized beam is focused on a target tissue, the power per area will be highly increased and the tissue can absorb significant thermal energy from the beam, which, in turn, results in heating. Traditionally, such hyperthermia has been used to warm tissues in physical therapy (Draper et al., 1995), to melt liposomes containing a drug in drug delivery (Tacker and Anderson, 1982), and to kill or ablate tissue (Kennedy et al., 2003; Madersbacher and Marberger, 2003; Huber et al., 2001). As a consequence, the role of heating the drugs, drug carriers, and/or the tissues receiving the drugs is accomplished by hyperthermia in drug delivery that is targeted.

Being an approximation of the second order wave equation, the Westervelt equation describes the propagation of a sound wave that is nonlinear and quasi-planar. The equation is derived from a thermoviscous fluid perspective in which expansions of mass conservation, momentum conservation, entropy balance, and thermodynamic state equations are incorporated. Certain assumptions underlie the derivation of the equation, among which the most essential ones are the homogeneity of propagation medium in composition and the uniformity of unperturbed density and pressure into three unique terms. The first two terms (in parentheses) represent diffraction and linear propagation and are the wave equation for linear propagation.

A thermoviscous loss in the fluid, or in