Nanobiomaterials in Cancer Therapy: Applications of Nanobiomaterials

Nanobiomaterials in Cancer Therapy

Applications of Nanobiomaterials

Edited by

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

Department of Biomaterials and Medical Devices, Faculty of Medical Engineering, University Politehnica of Bucharest, Bucharest, Romania

Table of Contents

Cover image

Title page

Copyright

List of contributors

Preface of the series

Preface

About the Series (Volumes I–XI)

About Volume VII

Chapter 1. Nanopreparations for skin cancer therapy

Abstract

1.1 Introduction

1.2 Skin Morphology

1.3 Types of Cancer

1.4 Non-Melanoma Skin Cancer

1.5 Melanoma Skin Cancer

1.6 Penetration Pathways of Skin

1.7 Drug Delivery Systems Applied to Skin Cancer Treatment

1.8 Liposomes

1.9 Nanoemulsions and Nanosuspensions

1.10 Polymeric Nanoparticles

1.11 Lipid Nanoparticles

1.12 Dendrimers

1.13 Photodynamic Therapy

1.14 Conclusions

References

Chapter 2. Silver nanoparticles in cancer therapy

Abstract

2.1 Introduction

2.2 Silver Nanoparticles

2.3 Synthesis

2.4 Shape

2.5 Silver Nanoparticles—Cancer Diagnosis and Treatment Applications

2.6 Conclusions

References

Chapter 3. Nanobiomaterials in cancer therapy

Abstract

3.1 Introduction

3.2 The Enhanced Permeability and Retention (EPR) Effect

3.3 Nanomaterials in Cancer Therapy

3.4 Chemotherapy-Based Nanoformulations

3.5 Multifunctional NPs

3.6 Cancer Therapy Using Natural Products: Nanochemoprevention

3.7 Cancer Stem Cells: A Nanotechnology Perspective

3.8 Conclusions

References

Chapter 4. Advances in nanobiomaterials for oncology nanomedicine

Abstract

4.1 Introduction

4.2 Organic Nanobiomaterials

4.3 Inorganic Nanobiomaterials

4.4 Combination of Nanotechnology with Photodynamic Therapy to Improve Cancer Treatment

4.5 Toxicity and Risk Management

4.6 Conclusions

Acknowledgments

References

Chapter 5. Nanobiomaterials: Emerging platform in cancer theranostics

Abstract

5.1 Introduction

5.2 Theranostics and Nanomedicine

5.3 Antibody as Theranostics

5.4 Challenges to Effective Cancer Theranostics

5.5 Conclusions and Future Perspectives

References

Chapter 6. Nanotherapeutics promises for colorectal cancer and pancreatic ductal adenocarcinoma

Abstract

List of Abbreviations

6.1 Introduction

6.2 Biology of Colorectal and Pancreatic Cancer

6.3 Current Clinical Treatment

6.4 Nanotherapeutics for Drug/Gene Delivery

6.5 New Nano-Based Strategies for Improved Delivery and Enhanced Bioavailability of Anticancer Drugs

6.6 Conventional and Nano-Based Prodrugs

6.7 Challenges and Perspectives

References

Chapter 7. Multifunctional drug nanocarriers facilitate more specific entry of therapeutic payload into tumors and control multiple drug resistance in cancer

Abstract

7.1 Introduction

7.2 Cancer and its Microenvironment

7.3 Characteristic Features of Tumor

7.4 Different Types of Nanocarriers

7.5 Tumor Targeting Through Nanocarriers

7.6 Types of Targeting Ligands

7.7 Challenges Associated with Targeting

7.8 Drug Resistance and How to Combat it with Different Nanocarriers

7.9 Major Mechanisms of Drug Resistance

7.10 Advantages of NP-Based Drug Delivery for Effective Cancer Therapy

7.11 Conclusions

References

Chapter 8. Nanoparticles as drug delivery systems of combination therapy for cancer

Abstract

8.1 Introduction

8.2 Liposomes for Combination Therapy

8.3 Polymeric DDS for Combination Therapy

8.4 Other Types of Polymeric DDS for Combination Therapy

8.5 Challenges for Clinical Trials

8.6 Conclusions

Acknowledgments

References

Chapter 9. Chitosan nanoparticles for efficient and targeted delivery of anticancer drugs

Abstract

9.1 Introduction

9.2 Nanomedicine

9.3 Future Perspectives

Acknowledgments

References

Chapter 10. Nanoformulations: A lucrative tool for protein delivery in cancer therapy

Abstract

10.1 Introduction

10.2 Challenges in Protein Delivery

10.3 The Vast Potential for Using Proteins in Cancer Therapy

10.4 The Enhanced Permeability and Retention (EPR) Effect

10.5 Methods for Protein Delivery

10.6 Commercial Aspects

10.7 Conclusions

References

Chapter 11. Nanobiomaterial-based delivery of drugs in various cancer therapies: Classifying the mechanisms of action (using biochemical and molecular biomarkers)

Abstract

11.1 Introduction

11.2 Polysaccharide-Based Nanoparticles

11.3 Chitosan–Drug Nanocarrier System in Cancer Therapy

11.4 Alginate Nanoparticles in Cancer Therapy

11.5 Pullulan Nanoparticles in Cancer Therapy

11.6 Heparin-Based Nanoparticles in Cancer Therapy

11.7 Starch Nanoparticles in Cancer Therapy

11.8 Protein-Based Nanoparticles

11.9 Silk Fibroin

11.10 Collagen

11.11 β-Casein Nanoparticles in Cancer Therapy

11.12 Albumin Nanoparticles in Cancer Therapy

11.13 Conclusions

References

Chapter 12. Dual-function nanocarriers with interfacial drug-interactive motifs for improved delivery of chemotherapeutic agents

Abstract

12.1 Introduction

12.2 Dual-Function Nanocarriers for Enhanced Cancer Therapy

12.3 Dual-Function Nanocarriers with Drug-Interactive Motifs for Improved Drug Delivery

12.4 Conclusions

References

Chapter 13. Nanotechnology for cancer therapy: Invading the mechanics of cancer

Abstract

13.1 Introduction

13.2 Nanomedicine: A Revolutionary Treatment Modality for Cancer

13.3 Tumor-Targeting Strategies

13.4 Personalized Nanomedicine

13.5 Conclusions

References

Chapter 14. Hadrontherapy enhanced by combination with heavy atoms: Role of Auger effect in nanoparticles

Abstract

14.1 Introduction

14.2 Improvement of Radiation Therapy by Different Methods

14.3 Auger Effects in Radiobiology: General Properties

14.4 Hadrontherapy Enhanced by Combination with High-Z Atoms

14.5 Hadrontherapy and Nanoparticles

14.6 Conclusions

14.7 Appendix

References

Chapter 15. Toxicity of silver nanoparticles obtained by bioreduction as studied on malignant cells: Is it possible to create a new generation of anticancer remedies?

Abstract

List of Abbreviations

15.1 Introduction

15.2 Studies of NE-AgNP Toxicity on Cultured Cells and Animals: General Description

15.3 Toxic Effects of NE-AgNPs Studied on Cancer Cells

15.4 The Mechanisms of Cytotoxicity of Biogenic AgNPs

15.5 Conclusions

References

Index

Copyright

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List of contributors

Udita Agrawal,     Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar, Madhya Pradesh, India

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

Bhawani Aryasomayajula,     Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA

Maria Vitória Lopes Badra Bentley,     School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

Archana Bhaw-Luximon,     ANDI Centre of Excellence for Biomedical and Biomaterials Research, University of Mauritius, Réduit, Mauritius

Ioana Raluca Bucur,     Department of Biomaterials and Medical Devices, Faculty of Medical Engineering, University Politehnica of Bucharest, Bucharest, Romania

Patrícia Mazureki Campos,     School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

Yu Cao,     Key Laboratory of Pesticide and Chemical Biology (Ministry of Education), College of Chemistry, Central China Normal University, Wuhan, PR, China

Samrat Chakraborty,     Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India

Ankan Choudhury,     Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India

Luciana M. De Hollanda,     Department of Internal Medicine, Hemocentro, School of Medical Science, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil

Surbhi Dubey,     Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar, Madhya Pradesh, India

Lopamudra Dutta,     Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India

Elena Mikhailivna Egorova,     Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, Russia

Norhaizan Mohd. Esa,     Universiti Putra Malaysia (UPM), Selangor, Malaysia

Yoshiya Furusawa,     Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan

Sharon E. Gao,     Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

Nowsheen Goonoo,     ANDI Centre of Excellence for Biomedical and Biomaterials Research, University of Mauritius, Réduit, Mauritius

Alexandru Mihai Grumezescu

Department of Biomaterials and Medical Devices, Faculty of Medical Engineering, University Politehnica 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

Nidhi Gupta,     Department of Biotechnology, The IIS University, Jaipur, Rajasthan, India

Dhanjay Jhurry,     ANDI Centre of Excellence for Biomedical and Biomaterials Research, University of Mauritius, Réduit, Mauritius

Said Ibragimovitch Kaba,     Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, Russia

Samikannu Kanagesan,     Materials Synthesis and Characterization Laboratory, Institute of Advanced Technology (ITMA), Universiti Putra Malaysia (UPM), Selangor, Malaysia

Katsumi Kobayashi,     Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization, Ibaraki, Japan

Aslan Amirkhanovitch Kubatiev,     Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, Russia

Claude Le Sech,     Institut des Sciences Molélculaires d’Orsay—ISMO Bât 351, Université Paris, Orsay Cedex, France

Mădălina Lemnaru,     Department of Biomaterials and Medical Devices, Faculty of Medical Engineering, University Politehnica of Bucharest, Bucharest, Romania

Song Li,     Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

Min Liu,     Key Laboratory of Pesticide and Chemical Biology (Ministry of Education), College of Chemistry, Central China Normal University, Wuhan, PR, China

Shiying Luo,     Key Laboratory of Pesticide and Chemical Biology (Ministry of Education), College of Chemistry, Central China Normal University, Wuhan, PR, China

Dipika Mandal,     Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India

Maria Minodora Marin,     Department of Biomaterials and Medical Devices, Faculty of Medical Engineering, University Politehnica of Bucharest, Bucharest, Romania

Ştefania Marin,     Department of Biomaterials and Medical Devices, Faculty of Medical Engineering, University Politehnica of Bucharest, Bucharest, Romania

Nishi Mody,     Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar, Madhya Pradesh, India

Laboni Mondal,     Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India

Shaker A. Mousa,     The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA

Jean Felix Mukerabigwi,     Key Laboratory of Pesticide and Chemical Biology (Ministry of Education), College of Chemistry, Central China Normal University, Wuhan, PR, China

Biswajit Mukherjee,     Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India

Radhakrishnan Narayanaswamy

Universiti Putra Malaysia (UPM), Selangor, Malaysia

Laboratory of Natural Products, Institute of Bioscience (IBS), Universiti Putra Malaysia (UPM), Selangor, Malaysia

Surendra Nimesh,     Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Ajmer, Rajasthan, India

Ashok Kumar Pandurangan,     Department of Pharmacology, University of Malaya, Kuala Lumpur, Malaysia

Padmanabhan Parasuraman,     Lee Kong Chian School of Medicine, Nanyang Technological University (NTU), Singapore

Kalyani C. Patil,     Institute of Cancer Sciences, University of Glasgow, Glasgow, Lanarkshire, UK

Mehdi Rajabi,     The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA

Lucinda V. Reis,     Department of Chemistry and CQ-VR, UTAD, Vila Real, Portugal

Antonello Santini,     Department of Pharmacy, Università degli Studi di Napoli Federico II, Napoli, Italy

Bhabani Sankar Satapathy,     Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India

Soma Sengupta,     Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India

Patrícia Severino,     Laboratory of nanotechnology and nanomedicine (LNMED), University of Tiradentes and Institute of Technology and Research, Aracaju, Brazil

Rajeev Sharma,     Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar, Madhya Pradesh, India

Amélia M. Silva

Department of Biology and Environment, University of Trás-os Montes e Alto Douro, Vila Real, Portugal

Centre for Research and Technology of Agro-Environmental and Biological Sciences (CITAB, UTAD), Vila Real, Portugal

Eliana B. Souto

Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Coimbra, Portugal

Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal

Selma B. Souto,     Department of Endocrinology and Metabolism, Hospital of Braga, Braga, Portugal

Mathangi Srinivasan,     The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA

Roxana Elena Ţiplea,     Department of Biomaterials and Medical Devices, Faculty of Medical Engineering, University Politehnica of Bucharest, Bucharest, Romania

Vladimir P. Torchilin

Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA

Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia

Noriko Usami,     Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization, Ibaraki, Japan

George Mihail Vlăsceanu,     Department of Biomaterials and Medical Devices, Faculty of Medical Engineering, University Politehnica of Bucharest, Bucharest, Romania

Ruchi Vyas,     Department of Biotechnology, The IIS University, Jaipur, Rajasthan, India

Suresh P. Vyas,     Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar, Madhya Pradesh, India

Jieni Xu,     Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

Jatinder Vir Yakhmi,     Department of Atomic Energy, Homi Bhabha National Institute, Mumbai, Maharashtra, India

Peng Zhang,     Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

Yuannian Zhang,     Key Laboratory of Pesticide and Chemical Biology (Ministry of Education), College of Chemistry, Central China Normal University, Wuhan, PR, China

Preface of the series

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

The era of nanosized materials is now considered the center of the evolution of future tools and emerging technologies with wide applications in industry, research, health, and beyond. Despite recent scientific progress, biological applications of nanomaterials are far from being depleted and current knowledge is limited by the poor access to significant data, but also by widespread and usually unfounded speculation. Although exhaustive, the current literature is difficult to reach and understand because of the specificity and strict focuses of researchers investigating different applications of nanomaterials.

In this context, the scientific series entitled Applications of Nanobiomaterials was motivated by the desire of the Editor, Alexandru Mihai Grumezescu, and others to bring together comprehensive, up-to-date, and relevant findings on the field of biological applications of nanostructured materials, to promote the knowledge and expand our vision regarding future perspectives. Even though the approached domain is quite specific and research-oriented, this multivolume set is easily intelligible for a wide audience including: under-graduate and post-graduate students, engineers, researchers, academic staff, pharmaceutical companies, biomedical sector and industrial biotechnologies. However, some basic knowledge of the field of materials science (nanobiomaterials, pharmaceutical industry, products for medicinal treatments, nanoarchitectonics for delivery of biological active molecules and release, bone implants and stomatology) and engineering is a requisite for understanding technical aspects.

The selected authors of each chapter are outstanding specialists in the field of nanobiomaterials, who have made impressive contributions in a specific area of research or applied area within the scope of this book.

Each of the 11 volumes of the series contains 15 chapters, addressing the most relevant and recent matters on the field of the volume.

The first volume, Fabrication and Self-Assembly of Nanobiomaterials, introduces the reader to the amazing field of nanostructured materials and offers interesting information regarding the fabrication and assembly of these nanosized structures. In Volume II, entitled Engineering of Nanobiomaterials, readers can easily find the most commonly investigated methods and approaches for obtaining tailored nanomaterials for a particular application, especially those with a great deal of significance in the biomedical field. In the following step, readers will discover the importance and the ways of modifying the surface of nanostructured materials to obtain bioactive materials, by reading Volume III, Surface Chemistry of Nanobiomaterials. Starting with Volume IV Nanobiomaterials in Hard Tissue Engineering and Volume V Nanobiomaterials in Soft Tissue Engineering, the biomedical applications of engineered nanomaterials are revealed and discussed, focusing on one of the most impacted fields, tissue engineering. Volume VI, Nanobiomaterials in Antimicrobial Therapy, highlights the potential of different nanostructured materials to be utilized in the development of novel efficient antimicrobial approaches to fight the global crisis of antibiotic inefficiency and emerging infectious diseases caused by resistant pathogens. Volume VII moves on to another key biomedical domain — cancer therapy. This volume, Nanobiomaterials in Cancer Therapy, describes current issues of cancer therapy and discusses the most relevant findings regarding the impact of nanobiomaterials in cancer management. Medical Imaging represents the focus of Volume VIII, while Volume IX deals with applications of Nanobiomaterials in Drug Delivery. Volume X, entitled Nanobiomaterials in Galenic Formulations and Cosmetics, refers to the perspectives highlighted by the utilization of nanosized functional biomaterials in the development of improved drugs and active principles for different biomedical industries. Finally, Volume XI is dedicated to the impact of Nanobiomaterials in Dentistry, which currently represents one of the most investigated and controversial domains related to the biomedical applications of nanostructured materials.

Due to their specific organization, each volume can be treated individually or as a part of this comprehensive series, which aims to bring a significant contribution to the field of research and biomedical applications of nanosized engineered materials.

Preface

Alexandru Mihai Grumezescu, http://grumezescu.com/, Department of Science and Engineering of Oxide Materials and Nanomaterials, University Politehnica of Bucharest, Bucharest, Romania, Department of Biomaterials and Medical Devices, Faculty of Medical Engineering, University Politehnica of Bucharest, Bucharest, Romania

About the Series (Volumes I–XI)

The increased fabrication of nanosized materials with applications on the biomedical field by using biomimetic and bio-inspired processes and formulations has recently led to a new concept, nanobiotechnology. This complex research brings together significant knowledge from physical, chemical, biological, and technological sciences in an applicative field.

Medical applications of nanobiomaterials range from the development of adequate scaffolds for tissue engineering to therapeutic nanostructures, such as targeted drug–delivery systems. The purpose of this multivolume set entitled Applications of Nanobiomaterials is to offer a broad, updated, and interdisciplinary point of view regarding the applications of these materials of the future medicine, starting with their fabrication, specific engineering, and characterization but also discussing about their impact in tissue engineering, antimicrobial and cancer therapies, and also the development of different medical and cosmetic use products. These books bring together the work of outstanding contributors who have significantly enhanced the basic knowledge and applicative concepts of this research field in their respective disciplines.

The multivolume set Applications of Nanobiomaterials contains 165 chapters, organized in 11 volumes which are ready to present a novel and up-to-date approach related to this intriguing domain. Each chapter was carefully composed and illustrated to highlight the relevance of nanobiomaterials on most biomedical fields, revealing the most recent applications on a specific domain. The whole set represents a great material for the academic community, starting with undergraduate and postgraduate students, researchers, engineers, and medical doctors, but also pharmaceutical companies and innovative biotechnologies.

These 11 volumes cover all relevant aspects related to the Applications of Nanobiomaterials as it follows:

Volume I: Fabrication and Self-Assembly of Nanobiomaterials

Volume II: Engineering of Nanobiomaterials

Volume III: Surface Chemistry of Nanobiomaterials

Volume IV: Nanobiomaterials in Hard Tissue Engineering

Volume V: Nanobiomaterials in Soft Tissue Engineering

Volume VI: Nanobiomaterials in Antimicrobial Therapy

Volume VII: Nanobiomaterials in Cancer Therapy

Volume VIII: Nanobiomaterials in Medical Imaging

Volume IX: Nanobiomaterials in Drug Delivery

Volume X: Nanobiomaterials in Galenic Formulations and Cosmetics

Volume XI: Nanobiomaterials in Dentistry

About Volume VII

Volume VII, Nanobiomaterials in Cancer Therapy, discusses the most important findings in the field of cancer treatment. Novel therapeutic approaches utilize nanobiomaterials able to significantly enhance drug-loading capacity, formulation stability, and improve the efficiency of the drug. This book highlights the fabrication methods of platforms for multimodal and combinatorial therapeutic options along with simultaneous and real-time cancer imaging and innovative approaches for oncology by passive or active pathways of multifunctional nanocarriers. Engineered nanobiosystems for cancer therapy, prevention, low cancer recurrence, or relapse are also revealed and discussed.

Volume VII contains 15 chapters, prepared by outstanding international researchers from the United States of America, Portugal, the United Kingdom, France, Mauritius, Romania, Russia, India, China, and Singapore.

In Chapter 1, Nanopreparations for Skin Cancer Therapy, Patrícia Mazureki Campos et al. give an overview regarding the alternative options for effective and convenient treatments of skin cancer, encompassing nanocarriers with focus on specificity and non-invasive approaches for enabling a cure.

Ştefania Marin et al., in Chapter 2, Silver Nanoparticles in Cancer Therapy, present an up-to-date review regarding the biological synthesis (by manipulating different microorganisms or plants) and also review available in vivo and in vitro tests performed on various types of cancer cells in order to correlate the physical properties of nanosilver and the administered doses with a satisfying effect regarding tumor inhibition.

Chapter 3, Nanobiomaterials in Cancer Therapy, prepared by Mathangi Srinivasan et al., focuses on current advances in the synthesis of nanoformulations of existing chemotherapeutic drugs or phytochemicals and the nanomaterials that are commonly used to engineer these systems for cancer therapy, prevention, reduced cancer recurrence, or relapse. Multifunctional nanoparticles that provide the platform for multimodal and combinatorial therapeutic options along with simultaneous and real-time cancer imaging are also reviewed.

In Chapter 4, Advances in Nanobiomaterials for Oncology Nanomedicine, Patrícia Severino et al. present an up-to-date review regarding nanobiostructures used for the development of innovative approaches for oncology by passive or active pathways.

Nishi Mody et al., in Chapter 5, Nanobiomaterials: Emerging Platform in Cancer Theranostics, present the role of nanomaterials in the detection and treatment of cancer, drawing attention to the promising potential of nanomaterials for applications in antitumor therapy. Metallic nanoparticles, polymeric nanoparticles, liposomes, dendrimers, carbon nanotubes, and quantum dots are some of the discussed examples of nanoformulations that can be used as multifunctional platforms for cancer theranostics.

In Chapter 6, Nanotherapeutics Promises for Colorectal Cancer and Pancreatic Ductal Adenocarcinoma, Archana Bhaw-Luximon et al. highlight the biologics of tumors and the intricacies of colorectal cancer and pancreatic ductal adenocarcinoma chemotherapy with a focus on emerging nanotherapeutics.

Biswajit Mukherjee et al., in Chapter 7, Multifunctional Drug Nanocarriers Facilitate More Specific Entry of Therapeutic Payload into Tumors and Control Multiple Drug Resistance in Cancer, present the main modalities for overcoming different physiological barriers of tumor targeting by using different types of multifunctional target-specific nanocarriers to facilitate more specific penetration of drugs into the tumor for better therapeutic outcome, with future directives to improve the frequency of translation of nanomedicine from laboratories to clinic.

In Chapter 8, Nanoparticles as Drug Delivery Systems of Combination Therapy for Cancer, Yuannian Zhang et al. give an overview of nanoparticles for drug combinations with elicit synergisms, including enhanced physical stability, and decreased side effects of drugs, since it can achieve unification of the pharmacokinetics and cellular uptake of various drug molecules with final improvements in their selective accumulation for the tumor by passive and/or active targeting mechanisms.

Chapter 9, Chitosan Nanoparticles for Efficient and Targeted Delivery of Anticancer Drugs, by Ruchi Vyas et al., shows the recent advancement in applications of chitosan nanoparticles for anticancer drug delivery and the factors dictating the efficacy of drug delivery and the main advantages of targeted delivery of anticancer drugs using nanotechnology: better delivery of poorly water-soluble drugs; cell- or tissue-targeted delivery of drugs; delivery of two or more drugs for combination therapy; imaging drug delivery sites in combination with imaging strategies; etc.

Chapter 10, prepared by Bhawani Aryasomayajula et al., Nanoformulations: A Lucrative Tool for Protein Delivery in Cancer Therapy, reviews the main technologies used for the delivery of proteins to tumors with a special focus on nanoformulations such as liposomes, nanogels, and antibody–drug conjugates. The recent advancements in protein nanoformulations are also explored, along with a brief discussion on their clinical aspect.

Ashok Kumar Pandurangan et al., in Chapter 11, Nanobiomaterial-Based Delivery of Drugs in Various Cancer Therapies: Classifying the Mechanisms of Action (Using Biochemical and Molecular Biomarkers), discuss the advantages, limitations, and efficacy of nanoparticles functionalized with biopolymers such as protein—silk, collagen, gelatin, β-casein, and albumin; protein-mimicked polypeptides—elastin-like polypeptide; polysaccharides—chitosan, alginate, pullulan, starch, and heparin; lipids, polymers—PLA, PLGA, and PCL; nanotubes—fullerene derivatives, in cancer therapy. The authors focus on reviewing the relevant changes in biochemical and molecular pathways of cancer cells during nanoparticle-mediated cancer therapy.

Chapter 12, Dual-Function Nanocarriers with Interfacial Drug-Interactive Motifs for Improved Delivery of Chemotherapeutic Agents, by Peng Zhang et al., presents up-to-date data regarding polymeric micelles that can take advantage of enhanced permeability and retention effect to specifically accumulate in different tumors. The authors discuss the development of dual-function carriers, which significantly enhance drug-loading capacity and formulation stability. These progresses may facilitate rational design of nanocarriers for improved drug delivery.

Kalyani C. Patil and J. V. Yakhmi, in Chapter 13, Nanotechnology for Cancer Therapy: Invading the Mechanics of Cancer, describe the particular characteristics of the tumor and tumor microenvironment and focus on the exploitation and understanding of these characteristics to design and develop nanocarriers and therapeutic nanotechnologies for selective tumor targeting.

N. Usami et al., in Chapter 14, Hadrontherapy Enhanced by Combination with Heavy Atoms: Role of Auger Effect in Nanoparticles, reveal the possibility of augmenting the radiobiological effects when the irradiated tissues are loaded with high-Z atoms by fast atomic ions contained in molecules or nanoparticles.

Chapter 15, Toxicity of Silver Nanoparticles Obtained by Bioreduction as Studied on Malignant Cells: Is It Possible to Create a New Generation of Anticancer Remedies?, prepared by Elena Mikhailivna Egorova et al., gives an overview of the results obtained regarding cytotoxic silver nanoparticles with the purpose of finding out whether these data obtained in recent years support the fact that there is a real prospect of obtaining remedies with high anticancer activity and a low level of toxicity toward normal cells and animal organisms.

Chapter 1

Nanopreparations for skin cancer therapy

Patrícia Mazureki Campos¹, Maria Vitória Lopes Badra Bentley¹ and Vladimir P. Torchilin²,³,    ¹School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil,    ²Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA,    ³Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia

Abstract

The incidence of skin cancer has grown over the decades for both non-melanoma and melanoma cancers. One out of every three diagnosed cases of cancer is non-melanoma skin cancer. Among skin cancers, melanoma remains a fatal disease. Surgical excision is often used to remove cancer, but topical therapy represents an appropriate treatment method, because it is not invasive, may reach a wide area of skin, and does not cause hypertrophic scars. The skin exerts a barrier function, mainly through the stratum corneum. Thus, topical application nanocarriers should overcome this and, through penetration pathways, reach the cancer and deliver anticancer drugs. Several types of carriers can improve drug/therapy limitations and may utilize local characteristics to increase efficacy. Also, photodynamic therapy works with photosensitizer delivered at the cancer site following irradiation, which destroys cancer cells. This chapter summarizes alternatives for effective and convenient treatments of skin cancer, encompassing nanocarriers with a focus on specificity and non-invasive approaches, enabling a cure.

Keywords

Non-melanoma skin cancer; melanoma skin cancer; topical therapy; nanocarrier; penetration pathways; photodynamic therapy; skin; cancer therapy; nanoparticle

1.1 Introduction

Skin cancer is divided into melanoma and non-melanoma cancers, with non-melanoma skin cancer (NMSC) subdivided into basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) (Eisemann et al., 2014). Despite NMSC not being reported in cancer registries, its incidence is estimated at 2–3 million cases per year, according to the World Health Organization (2011). Most of the NMSC cases can be treated, however, melanoma cancer represents less than 2% of all skin cancer cases, but accounts for the highest number of skin cancer deaths, with increasing incidence rates over the last year (American Cancer Society, 2014).

The prevalence of skin cancer is higher in people of European descent and those who live in equatorial latitudes, compared to people of Asian, African, and Hispanic descent (Agbai et al., 2014). In addition, NMSC is the most diagnosed cancer for white people worldwide, with BCC being four times more common than SCC (Chummun and McLean, 2014). However, there are reports of increasing morbidity and mortality in minority populations (Hu et al., 2009; Agbai et al., 2014).

This increase in skin cancer leads to issues related to awareness of and the main causes correlated with this type of cancer. The risk factors for skin cancer, in general, are as follows: exacerbated exposure to ultraviolet (UV) radiation; photoaging; sun sensitivity; Fitzpatrick skin type, defined as people with difficulty tanning, natural blond or red hair color; and conditions that suppress the immunologic system. However, the main risk factors for melanoma are family or personal histories and presence of atypical nevi (Lomas et al., 2012; Federman et al., 2013; American Cancer Society, 2014).

Skin cancer is a public health problem because it is the most common worldwide malignancy and encompasses the entire population, including all socioeconomic and demographic cohorts, covering the entire lifespan (Lomas et al., 2012; Gordon, 2013). Therefore, the primary preventative care recommendation is photoprotection by wearing clothes that cover the skin against solar exposure and using sunscreens in adequate amounts on skin to decrease incidence (Federman et al., 2013).

1.2 Skin Morphology

The skin is the largest and outermost organ of the body and exerts a vital role in maintaining homeostasis. This task is performed by a network of cells that interact among themselves. The skin protects the body from microorganisms, chemical and toxic products, as well as from the surrounding environment (Lai-Cheong and McGrath, 2009; Mathes et al., 2014). The barrier function of the skin is, in particular, played by the stratum corneum, the uppermost layer of the epidermis, which is composed of dead, cornified (protein-rich) cells within a matrix of intercellular lipids (Karadzovska et al., 2013). This layer is formed during epidermis turnover from cells that begin at the basal layer, differentiate, and end at the stratum corneum in a flattened appearance (Mathes et al., 2014). Moreover, by its constitution, the stratum corneum reduces water loss from the body (Lai-Cheong and McGrath, 2009).

In general, the skin is divided into three layers: epidermis, dermis, and hypodermis. The epidermis is a stratified squamous epithelium formed by keratinocytes that originate at the basal layer by mitosis of epidermal stem cells, where there are also melanocytes. These cells migrate to the spinous layer forming polyhedral cells connected by desmosomes. Langerhans cells (responsible for immune response) are found in this same layer. Keratinocytes appear with intracellular granules of keratohyalin (future keratin), constituting the granular layer. Finally, the cells, now called corneocytes, pass through nuclei and cytoplasm loss, wherein keratin filaments align between intercellular lipids as ceramides and fatty acids, forming the stratum corneum (Lai-Cheong and McGrath, 2009; Venus et al., 2010).

Melanocytes are dendritic cells derived from the neural crest that migrate during embryogenesis to the basal layer of the epidermis. These cells synthesize melanin inside melanosomes and transfer to neighboring keratinocytes (Park et al., 2008). Melanin is a pigment that protects the skin against ultraviolet radiation and its effects, it is scattered on the perinuclear area forming caps, which prevent DNA damage (Slominski et al., 2004).

Langerhans cells are resident immune cells inside the skin; they constitute the first barrier for invading pathogens and act as sentinels. When activated in response to inflammatory cytokines produced by keratinocytes, they traffic toward the draining lymph nodes, where T-cell activation occurs, where T cells become memory T cells with expression of surface markers allowing skin accumulation. In addition, Langerhans cells can participate in allergic processes (Callard and Harper, 2007; Hieronymus et al., 2014).

The dermis is under the epidermis, provides elasticity and resilience to the skin, and interfaces through the dermal–epidermal junction, a region with an intricate network of proteins and glycoproteins that provides adhesion. The dermis is subdivided into papillary and reticular layers, composed of: collagen and elastic fibers, ground substance (proteoglycan macromolecules), and cells, including fibroblasts, mast cells, plasma cells, dermal dendritic cells, and histiocytes. Inside the dermis there are blood vessels, lymphatic channels, and sensory nerves, as well as sweat glands (eccrine and apocrine), which are responsible for thermoregulatory sweating and excretion of other fluids. The hair follicle is an invagination of the epidermis toward the dermis with dermal papilla on its base, richly vascularized and enervated, associated with a sebaceous gland (Lai-Cheong and McGrath, 2009). The hypodermis, composed of fatty tissue surrounded by dermis tissue, stores fat, makes the body thermoregulate, and absorbs physical shock (Mathes et al., 2014).

1.3 Types of Cancer

The origin of skin cancer is multifactorial, but the main etiological factor is ultraviolet radiation. Skin cancer incidence increases with aging, a consequence of cumulative solar exposure (Gordon, 2013). Ultraviolet exposure is related to both melanoma and NMSC, including BCC and SCC, because ultraviolet radiation causes DNA damage, gene mutations, immunosuppression, oxidative stress, and inflammatory responses, all of which are causes directly linked to skin cancer genesis (Narayanan et al., 2010; Kim and He, 2014). UVB and UVC radiation are associated with sunburn and carcinogenesis, UVA also induces sunburn and intensifies UVB effects, but is less mutagenic. However, both UVB and UVA may promote tumor genesis by selective immunosuppression (Robinson-Bostom and McDonald, 2002).

The development of skin cancer originates with premalignant lesions such as actinic keratosis, also called solar keratosis, which appears mainly in skin regions exposed to sun, and are characterized by small, raised, scaly erythematous spots surrounded by telangiectasia, hyperpigmentation, and yellow areas of discoloration (Figure 1.1a). Another sign is Bowen’s disease (Figure 1.1b), known as SCC in situ, which is preponderant in women and often appears on the legs, distinguished by well-demarcated scaly and erythematous plaques. In addition, Bowen’s disease can emerge in the mucous membrane and, potentially, progress to invasive SCC (Robinson-Bostom and McDonald, 2002; Gordon, 2013; Chummun and McLean, 2014).

Figure 1.1 Examples of premaligant lesions: actinic keratosis (a) –defined papules with adherent scale on dorsal hand; Bowen’s disease (b) –well-demarcated erythematous plaque; lentigo maligna (c) –lesion with superficial spreading and irregular color/borders near eyebrow. Courtesy of dermatologist Dr. Aguinaldo Bonalumi Filho.

Likewise, another type of premalignant lesion is lentigo maligna (Figure 1.1c), which is characterized by abnormal melanocytes restricted to the epidermis. It occurs in sun-exposed areas and may advance to lentigo maligna melanoma (Gordon, 2013; Chummun and McLean, 2014).

For patients with early detection of these premalignant lesions, it is possible to start topical treatment with substances such as retinoids, 5-fluorouracil, imiquimod, and ingenol mebutate, to prevent the development to carcinoma of these lesions with complete clearance and a good cosmetic effect (Amini et al., 2010; Micali et al., 2014).

1.4 Non-Melanoma Skin Cancer

BCC is the most common skin cancer in the Caucasian population. It accounts for 80–85% of NMSC and rarely metastasizes to other organs. However, SCC accounts for 15–20% and easily invades other tissues with higher mortality (Simoes et al., 2015).

BCC (Figure 1.2a) is a malignant tumor of germinative cells in the basal layer of the epidermis and/or the root sheaths of the outer hair follicle. These tumors grow aggressively causing wide damage, but do not spread to distant areas. The main risk is cumulative UVB radiation (280–320 nm), which penetrates to the epidermis and provokes direct damage to DNA and RNA, inducing covalent bonds between pyrimidines, generating photoproducts (Madan et al., 2010; Kolk et al., 2014). If this DNA damage is not repaired, it can lead to a genome mutation, contributing to skin carcinogenesis. In order to maintain genome stability, the cells have repair mechanisms, such as nucleotide excision repair, and are critically involved in recruiting photoproducts (Kim and He, 2014).

Figure 1.2 Examples of NMSC lesions: (a) –BCC with nodulocystic lesion showing telangiectasia and ulceration on the top cheek; (b) –SCC with lesion presenting infiltration to connective and subcutaneous tissues near lower lip. Courtesy of dermatologist Dr. Aguinaldo Bonalumi Filho.

BCC is often found on the nose, ears, face, shoulders, and back. The following are subtypes of BCC: nodular lesions with necrotic centers; superficial BCC as pink patches; sclerosing BCC as yellowish plaques; and pigmented BCC as dark lesions (Lacy and Alwan, 2013). In fact, BCC is a typical primary efflorescence in papula form with telangiectasia that is slow-growing. Further, at advanced stages, ulceration and erosion are observed, with tumor growth potentially reaching cartilaginous and bone tissues (Kolk et al., 2014).

SCC (Figure 1.2b) is the second most common skin cancer in Caucasians, appearing in sun-exposed areas, and the most common neoplasm in non-white people, appearing in sun-protected areas subjected to frequent external trauma (Robinson-Bostom and McDonald, 2002). It is a malignant proliferation of squamous cells—epidermal keratinocytes with a high potential of metastasis to lymph nodes and other organs (Ogden and Telfer, 2009). The main factor is UV radiation that produces mutations in the p53 tumor suppressor gene, which functions as a tumor suppressor by inducing apoptosis of cells that have DNA damage, the kind of alteration that is recurrent in SCC (Robinson-Bostom and McDonald, 2002).

SCC lesions emerge in areas with long-term UV exposure. In general, these lesions are predisposed to actinic keratosis (irregular arrangement of epidermis from atypical cells) or immunosuppressed status, but also arise from other etiologic factors such as chronic inflammation or degenerative influences. Lesions possess a tumor width larger than 2 cm and depth greater than 6 mm and exhibit infiltration to connective and subcutaneous tissues, positive margins, high mitotic activity, and ulceration (Kolk et al., 2014; Mavropoulos et al., 2014). When a complete invasion of epidermis occurs, this constitutes an intraepithelial carcinoma or transitional epithelium, which are considered in situ carcinomas (Kolk et al., 2014). According to the World Health Organization, SCC can be classified into spindle-cell SCC (aggressive behavior), adenoid (pseudoglandular) SCC, verrucous carcinoma (favorable diagnosis), keratinizing SCC, basosquamous SCC, and lymphoepithelioma-like carcinoma (Heenan et al., 1996). The choice of SCC tumor removal depends on multiple factors including size and site of the lesion, clinical and histological type, and treatment costs (National Collaborating Centre for Cancer, 2010).

Despite UV radiation being the principal risk factor associated with NMSC, there are other related factors, such as human papillomavirus, iatrogenic immunosuppression, HIV/AIDS, non-Hodgkin lymphoma, photosensitizing drugs (e.g., fluoroquinolone antibiotics), and occupational factors (Madan et al., 2010).

The management of NMSC must consider surgical and non-surgical options focusing on complete tumor removal, producing a cure, being as minimally invasive as possible and maintaining an aesthetic result. Excisional surgery has been employed for the excision of NMSC in an outpatient procedure with the aim of complete tumor removal, which offers shorter healing, in addition to histologic examination of tissue. Moreover, other techniques including curettage, electrodesiccation, and Mohs micrographic surgery provide detailed microscopic visualization of tissue removed with guaranteed tumor clearance. However, when a wide area is affected, by potential disfigurement and functional impairment, non-surgical options could be used (Madan et al., 2010; Chummun and McLean, 2014; Parikh et al., 2014).

If an early NMSC diagnosis is made based on patient and tumor characteristics, it is possible to regard destructive treatment options in monotherapy or conjugated therapies such as topical modalities, photodynamic therapy, cryosurgery, and radiotherapy. Among the non-surgical options, the topical therapy is convenient, offers good cosmesis with less chance of scarring and the possibility of treating large areas. One example of a topical therapy approved by the US Food and Drug Administration (FDA) for NMSC is the immunomodulating agent imiquimod 5%. However, it is necessary to have patient compliance and to consider costs for long-term treatment and be aware of producing false-negative margins, which impairs the efficacy of surgery excision (Galiczynski and Vidimos, 2011; Lazareth, 2013).

1.5 Melanoma Skin Cancer

Among melanoma subtypes, melanoma skin cancer (MSC) is the most prevalent, accounting for approximately 90% of cases, occupying 19th position for cancer worldwide (Ali et al., 2013) and it could be considered the most dangerous form of skin cancer. The incidence of MSC has been increasing in lighter-skinned people, but pigmented people are usually diagnosed in advanced stages, which contributes to the high mortality rate associated with MSC (Stubblefield and Kelly, 2014). Notably, the total incidence is higher in elderly white women (Ingraffea, 2013). If melanoma is detected early surgical removal can provide a cure (Shackleton and Quintana, 2010).

Several etiological factors are associated with MSC development, including environmental and genetic factors. Skin pigmentation is a decisive factor that influences the appearance of malignant changes, and interactions between genetic and environmental factors bring different rates of incidence (Ali et al., 2013). The patterns of sun exposure govern the site origin of lesions in the head, neck, or extremity, which are related to chronic exposure and, at the same time, period UV exposure, with truncal lesions (Ingraffea, 2013). The transition of normal melanocytes to melanoma cells involves several steps, which modify the processes of cell proliferation, differentiation, and death, until the progressive genetic mutations result in the carcinogenic effects of UV radiation. Furthermore, high nevus counts present in sun-protected areas subject to intermittent UV radiation can develop into MSC (Mandala and Voit, 2013).

The MSC morphology (Figure 1.3) appears as patches, plaques, nodules, and pigmented tumors, but scarcely as a polypoidal with a stalk (Plotnick et al., 1990; Cockerell, 2012). In general, MSC lesions have a diameter greater than 6 mm; however, smaller lesions could be diagnosed, which arise on sun-exposed skin (Cockerell, 2012). The prognosis is defined by histological characteristics such as tumor thickness; lesions smaller than 1 mm have a good prognosis, with 10-year survival, dropping to 54% survival for larger than 4 mm. Furthermore, epithelial ulcerations in the initial examination should be considered a worse prognosis (Balch et al., 2001; Green et al., 2012). Additional features such as high mitotic rate, tumor vascularity, and lymphovascular invasion contribute to the increased risk of metastasis (Ali et al., 2013).

Figure 1.3 Examples of MSC lesions: (a) –Papule occupied by accumulation of proliferative melanocytes present in the back; (b) –lesion near the ear indicating asymmetry and irregular color. Courtesy of dermatologist Dr. Aguinaldo Bonalumi Filho.

There are four types of MSC: (i) superficial spreading, which indicates that the tumor is flat, slow-growing, with irregular borders and pigmentation, enlarging in radial directions, and occurring in areas of intermittent sun exposure; (ii) nodular, which indicates that the tumor enlarges as a nodule that may ulcerate and hemorrhage and can present on any area; (iii) lentigo maligna, present on chronic sun-exposed areas of the head, neck, and forearms, with large macules with variegated pigmentation and irregular borders; and (iv) acral lentiginous, indicating areas with variegated pigmentation that are very slow-growing and usually appear on the palms and soles (Scolyer et al., 2011; Ingraffea, 2013).

Molecular characteristics are, in part, related to the frequency of BRAF or NARS and KIT mutations and based on the pattern of UV exposure. BRAF mutations often appear in intermittent UV exposure and KIT mutations in chronic or unexposed skin (Mandala and Voit, 2013). Most MSCs have activated mutations on BRAF or NARS proto-oncogenes; these oncogenic modifications may serve as targets to improve therapy (Broekaert et al., 2010). BRAF mutations located on the kinase domain promote an increase in kinase activity and substitution of valine to glutamate in the glycine-rich loop, but reports suggest that this isolated mutation is insufficient and other genetic mutations are necessary to induce the entire transformation of melanocytes (Mandala and Voit, 2013). Regarding the impact of the BRAF mutation on MSC, data indicate that this mutation emerges in young people without cumulative UV exposure, but for people with no mutations, high doses of UV radiation are required for MSC to occur (Curtin et al., 2005; Bauer et al., 2011). Overall, the management of the BRAF mutation is a turning point for controlling the spread of disease (Mandala and Voit, 2013), and for those who do not carry a known mutation for understanding the growth and metastasis of MSC, research efforts should be made to improve disease therapy (Shackleton and Quintana, 2010).

Currently, there is no topical treatment approved by the FDA for MSC, and the recommendation is excisional surgery associated with systemic immunotherapy, Yervoy® (Ipilimumab), or oral tablets of Zelboraf® (Vemurafenib) (Zhang et al., 2013).

1.6 Penetration Pathways of Skin

The skin is a selective and effective membrane of the body that protects from chemical penetration. This barrier function is fulfilled by the stratum corneum, which is considered a rate-limiting pass to permeate therapeutic agents applied on the skin. The stratum corneum can be expressed as a two-compartment model, represented by corneocytes, keratin-filled cells, embedded into a lipid matrix, composed of ceramides with nine subtypes, cholesterol, and free fatty acids. The architecture of stratum corneum provides great diffusional resistance, which is important in establishing a steady-state drug flux to promote drug entry (Michniak-Kohn et al., 2005; Barry, 2006). This compartmental model, which constitutes a tortuous way, was proposed by Elias (1983).

When a substance is at the skin surface (Figure 1.4), there are four options for entry to reach the viable epidermis, which are as follows: (i) via hair follicles, which are associated with sebaceous glands; (ii) via intracellular mechanisms; (iii) via intercellular mechanisms; and (iv) through eccrine sweat ducts (not shown in Figure 1.4). The easy way to enter the skin would be follicular, but this pathway occupies only 0.1% of total superficial area. By the density of appendageal area, however, it works as a shunt in the short term; previously, steady-state diffusion, for ions and polar molecules, also for targeting of polymers and colloidal particles (Michniak-Kohn et al., 2005; Barry, 2006).

Figure 1.4 Scheme of penetration pathways through the skin: intracellular, intercellular and follicular. The upper right inset is a close-up of the stratum corneum showing the intracellular pathway and the tortuous intercellular pathway. Reprinted from Current Opinion in Colloid & Interface Science, vol. 17/issue 3, Bolzinger, M.A., Briançon, S., Pelletier, J., Chevalier, Y. Penetration of drugs through skin, a complex rate-controlling membrane, p. 10, Copyright (2012), with permission from Elsevier.

The skin offers an alternative pathway for allowing topical application of a sustained drug delivery system into the blood circulation, decreasing the side effects of conventional administrations (oral and parenteral). In addition, developing and optimizing drug entry through loading into topical products has been a good strategy because it is possible to offer more efficacy for delivery in and through the skin by this route (Lademann et al., 2009; Bolzinger et al., 2012).

In designing therapeutic products for use through the skin, it should be recalled that, first, the stratum corneum displays barrier properties (lipid domain, as a gel-phase membrane with complex arrangement). Second, the viable epidermis is predominantly a hydrophilic layer (70% water). Thus, hydrophilic drugs permeate into the skin through the intracellular pathway, inside the stratum corneum, infiltrating among several sheets of corneocytes (through lipid head group regions), unlike hydrophobic drugs, which may easily enter the stratum corneum (through lipid tails), forming a reservoir due to the aqueous domain of the subsequent layer. In other words, there is a relationship between the skin constitution and the physicochemical properties of a drug including the following: (i) molar mass (MW) related to the diffusion coefficient; (ii) number of hydrogen bonds established in the route; and (iii) octanol–water partition coefficient (log Ko/w), which reveals the stratum corneum/water partition. Further, passive diffusion through the skin is accomplished by the concentration gradient of substances, after a sequence of interactions with the keratin of corneocytes and lipid partitions (Guy and Hadgraft, 1985; Naik et al., 2000; Liu et al., 2011). It is possible to calculate drug permeability by calculating the permeability coefficient (log kP) based on the Potts–Guy relationship log kP (cm/h)=−2.7+0.71 log Ko/w−0.0061 MW (Potts and Guy, 1992).

In addition, another theoretical aspect, but no less important, is drug permeation across the stratum corneum driven by the equation J=(Dm. Cv. P)/L described by Fick’s law, where J is the flux, Dm is the diffusion coefficient of the drug in the membrane, Cv is the drug concentration in the vehicle, P is the partition coefficient, and L is the stratum corneum thickness. Therefore, through this equation, it is possible to identify ways to change the drug flux, which can be altered by using chemical penetration enhancers contained in the formulation, influencing the Dm, or by using nanocarriers with high drug concentrations that will modify Cv (Barry, 2006).

Drug transport across the skin implies diffusion inside the intercellular region through interspersing the lipids surrounded by the corneocytes. The intercellular pathway is considered important for drug entry inside the skin (Prausnitz and Langer, 2008). In order to increase the skin permeability and increase the thermodynamic activity of the drug, different methods have been used, such as, drug delivery systems (nanotechnology-based systems), stratum corneum modification (chemical enhancers—fatty acids, alcohols, and surfactants), and electrically assisted methods (ultrasound, iontophoresis, electroporation) (Alvarez-Roman et al., 2004; Barry, 2006; Polat et al., 2011; Prow et al., 2011; Tomoda et al., 2011).

Recent experiments have demonstrated that the follicular pathway works as an efficient long-term reservoir for topical products. In addition, the development of drug delivery systems has focused on this, by considering it as a target along with its morphologic characteristics, allowing for access to blood circulation and/or deep skin layers (Lademann et al., 2009). Other studies have shown that appendages are important for small molecules, because the flux measured was three times lower where the appendages were absent, compared to normal skin (Illel et al., 1991).

After penetration through the main barrier, the stratum corneum, the molecule encounters another environment, less restrictive for passive diffusion, but which can also provide a different mechanism of transport such as binding and sequestration, active transport, and metabolism. In addition, through the epidermal–dermal junction, the dermis is accessed, which is enhanced through vascularization and the lymphatic system, with significant drug transport and distribution in the skin, both facilitating drug clearance (Jepps et al., 2013).

Nanocarriers are interesting tools for skin drug delivery, particularly for liposomes, polymeric and lipid nanoparticles, because they can form a film on the skin and provoke occlusion effects, producing local drug delivery to the epidermis and dermis and systemic action by deep penetration (Bolzinger et al., 2011). Another issue is the interaction between the nanoparticles and stratum corneum and, consequently, lipid disruption and nanocarrier integrity, as observed with lipophilic carriers. Moreover, particle stiffness alters skin permeability, establishing that rigid particles, such as polymeric and lipid nanoparticles, do not infiltrate intact skin, but that deformable particles, such as transfersomes and ethosomes, can pass through the interspaces of the stratum corneum (Bolzinger et al., 2012).

Considering that particles in the size of hundreds of nanometers can penetrate deeper into hair follicles and persist for 10 days, much longer when considering the stratum corneum and isolated substances, if massage is applied, they are a good option for topical skin therapy (Lademann et al., 2007). Overall, nanocarriers can locate the drug within the hair follicle, where the drug is released and can penetrate independently. For example, nanoparticles 40 nm in diameter were found inside Langerhans cells in an excised human skin model (Lademann et al., 2011). In the same way, nanocarriers can be used as chemical enhancers by increasing the drug solubility and partitioning into the skin (Prausnitz and Langer, 2008).

Several researches have used normal skin, but little attention has been paid to absorption in damaged skin. Diseases that modify skin integrity, such as the stratum corneum in wounds and inflammation, or disturbed epidermal cell differentiation in NMSC, can lead to damaged skin. The permeation profiles of nanoparticles in damaged skin models have been created to mimic these pathological conditions as stripped human skin ex vivo, removal of stratum corneum as disruption of a physical barrier (Alnasif et al., 2014) and a three-dimensional human SCC construct model, which includes hyperkeratosis and epidermal atrophy with less functional barrier (Obrigkeit et al., 2009). Within this method, higher permeation of Nile red loaded into a flexible nanocarrier was observed for stripped skin compared to normal skin, and in 6 h, the stripped skin already presented increased nanocarriers into viable skin layers, an effect that was more pronounced after 24 h. This was not observed for normal skin, thus showing that disrupted skin exhibits less of a barrier. The same situation was encountered for normal and SCC construct models, more Nile red was delivered to diseased skin (Alnasif et al., 2014).

1.7 Drug Delivery Systems Applied to Skin Cancer Treatment

Nano-sized drug delivery systems have huge potential for the treatment of cancer cells because they are able to deliver drugs into tumors by the enhanced permeability and retention (EPR) effect that results from high permeability of tumor vasculature (Torchilin, 2011). In search of selective cancer treatment, using local features of tumor is a specific way of using abnormalities in favor of anticancer target therapy based on nano-sized systems (Greish, 2010). In this context, specific binding to target cancer cells or utilizing the tumor microenvironment characteristics open new opportunities to improve the efficacy of cancer treatment, decreasing the harm done to healthy cells (Allen and Cullis, 2004; Tiwari et al., 2012).

Numerous factors stimulate the utilization of nanomedicine for drug delivery, such as increased drug solubility, modulating drug release, protecting drugs against degradation, avoiding premature metabolism, cooperating with biodistribution, and reduced side effects. In addition, nanoparticles applied to cancer therapy can alter limitations that are frequently common for chemotherapeutic agents, such as lack of specificity and high toxicity, which generates pronounced side effects (Díaz and Vivas-Mejia, 2013).

Nanocarriers are defined as a system that loads drugs incorporated into organic or inorganic matrixes with a size of 10–1000 nm. They can have different shapes, surface charge, functionality, and stability, as well as several in vivo applications. Recently, theranostic particles have been developed, which encapsulate drugs/imaging agents, allowing both treatment and monitoring of the cancer, as well as stimuli-responsible carriers, which are sensitive to physical and chemical stimuli releasing the drug (Lim et al., 2013b). There are several possibilities for building a specific and multifunctional nanocarrier, considering the characteristics of the pathology, action site and carrier systems, some of these options are presented in Figure 1.5.

Figure 1.5 Representation of multifunctional nanocarrier where drugs A and B can be loaded into a liposome or micelle showing several possibilities for improving the selectivity and efficacy of the system. PEG, poly(ethylene glycol). Reprinted from Nature Reviews Drug Discovery, vol. 13/issue 11, Torchilin, V.P., Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery, p. 14, Copyright (2014), with permission from Elsevier.

A good rational design for drug delivery focused on skin cancer therapy should involve tumor targeting because cancer cells express particular features that can be useful; for example, differences in the expression pattern of receptors between normal and cancer cells, which become a custom drug delivery system (Torchilin, 2014). One example of this would be to use receptors involved in NMSC, such as the ErbB family of receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR), HER2, HER3, HER4, which, structurally, have a conserved cytoplasmic catalytic domain, a hydrophobic transmembrane domain, and a glycosylated extracellular ligand-binding domain. These receptors participate in the tumorigenesis, contributing to their overexpression (Salomon et al., 1995; Krähn et al., 2001). Therefore, the construction of a drug delivery system based on receptor overexpression is possible if a specific binder (e.g., monoclonal antibody, peptide) is present on the nanocarrier as a surface modification and attaches to target tissue or cells, thus demonstrating the concept of active targeting (Sawant and Torchilin, 2012; Torchilin, 2014).

Among the nanocarriers utilized in application to skin cancer therapy are those with transdermal, topical, and systemic applications. Specifically, these carriers could be polymeric nanoparticles, solid lipid nanoparticles, nanoemulsions, nanosuspensions, liposomes, micelles, silica nanoparticles, dendrimers, gold nanoparticles, and magnetic nanoparticles (Dianzani et al., 2014; Simoes et al., 2015). A promising technology, magnetic nanoparticles, works through an external alternating magnetic field to transform their magnetic energy into heat as a dynamic response to a dipole with their magnetic moments. The hyperthermia provokes cell death, and this delivery system can also load drugs, which decreases dosage by the synergy added by the magnetic effect (Lim et al., 2013b).

A well-designed formulation for skin cancer treatment through topical application is indispensable, which would be able to increase drug penetration across the stratum corneum, as well as deliver the drug into deep skin layers because tumors are located in deep sites. At the same time, it is important to consider that molecules used to treat skin cancer are hydrophilic and of high molecular weight and are thus hard to get into the skin (Taveira and Lopez, 2011).

1.8 Liposomes

Liposomes are a vesicular-form drug delivery system composed of phospholipids in a bilayered membrane with aqueous phase inside and between the lipid bilayers. They offer biocompatibility, biodegrability, and low toxicity. Liposomes are able to encapsulate lipophilic compounds in the lipophilic layer membrane and hydrophilic substances in the aqueous core. They do not provoke immune system activation and easily incorporate new substances added to lipid mixtures or by different preparation methods. They can be multilamellar (several concentric bilayers) with size from 500 to 5000 nm or unilamellar with sizes ranging from approximately 100 nm (small) to 200–800 nm (large) (Voinea and Simionescu, 2002; Torchilin, 2005).

If they have an antibody attached to the external membrane, liposomes become susceptible to accumulation on specific target sites. In addition, they can deliver their loads inside the cells or to individual cell compartments (Torchilin, 2005) or, with PEG-binding on the surface, can increase specificity, accumulating near tumor vessels (Yuan et al., 1994). Related to biocompatibility with the stratum corneum, liposomes have high affinity, are biodegradable, and are able to increase drug delivery to the skin (Rahimpour and Hamishehkar, 2012).

Liposomes with different compositions were developed in order to improve the stability and modify the penetration across membranes, such as the stratum corneum. These new generations are transfersomes®, niosomes, and ethosomes®, which are composed of phosphatidylcoline and sodium cholate, phosphatidylcoline and ethanol, and non-ionic surfactants, respectively. They are flexible and deformable, passing through the pores present on the skin surface, and carry the drug toward deep skin layers (Santana and Zanchetta, 2011).

There are reports of drugs encapsulated in liposomes to treat skin cancer such as aloe-emodin for NMSC treatment (Chou and Liang, 2009), bleomycin in ultradeformable liposomes to treat SCC (Lau et al., 2005), cationic liposomes carrying small interfering RNA (Yano et al., 2004), and T4N5 molecules with amphiphilic phospholipids topically applied to repair DNA enzymes to prevent skin cancer. This kind of entrapment prevents the thermal degradation of the molecule (Ceccoli et al., 1989).

Few reports describe topical application of liposomes with chemotherapy; instead, intravenous administration is described. Some examples are cisplatin-alginate for targeted delivery to EGFR-positive ovarian cancer cells (Wang et al., 2014) and oxaliplatin into PEGylated liposomes to improve antitumor activity (Nakamura et al., 2014). The topical application was related to the use of pro-drug 5-aminolevulinic acid (5-ALA) for photodynamic therapy, it involved liposomes and ethosomes® loading 5-ALA into the skin, and both showed increased 5-ALA entry. Moreover, ethosomes® had a better penetration into the skin in in vivo studies (Fang et al., 2008).

Ethosomes® carrying chemotherapy substances have been described. Studies of ethosomes® containing 5-fluorouracil for transdermal delivery in in vitro skin penetration showed that this delivery system was able to increase the amount of 5-fluorouracil in human skin and hypertrophic scar tissue, and is considered highly efficient for skin penetration (Zhang et al., 2012). Other ethosomes® containing paclitaxel were able to perform topical delivery of the drug in the stratum corneum–epidermis membrane model and increase its antiproliferative activity in an SCC model compared to unbound drug, suggesting a potential treatment for SCC (Paolino et al., 2012).

Niosomes, in topical delivery, were loaded with 5-fluorouracil for treatment of skin cancer. This system was able to substantially increase the drug penetration in human stratum corneum and epidermis membranes, as well as improve the cytotoxic effect on SKMEL-28 (human melanoma cells) and HaCaT (non-melanoma skin cancer cells), showing its potential for topical application and enhancing the drug cytotoxic property (Paolino et al., 2008).

In summary, liposomes and new generations