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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Sprache: Englisch
INTEGRATION OF BIOMATERIALS FOR GENE THERAPY Brings industrial practitioners and researchers together to discuss how the deeper integration of biomaterial platforms could play a significant role in enabling breakthroughs in the application of gene editing for the treatment of human disease. This book comprises research and review articles from leading researchers with multidisciplinary experience. It discusses many broad topics, including nanoparticle-enabled gene therapy, inorganic nanocarrier-based gene delivery, non-viral delivery of nucleic acid, biocompatible hydrogels, silk, and polysaccharides-based gene delivery. Other gene delivery topics discussed include the use of smart and engineered biomaterials, combined therapy with growth factors and cell transportation, and the prospects and challenges in the treatment of different diseases, including cancer. This book bridges the knowledge of pharmaceutics, engineering, basic science, and clinical research fields in a way that will help the research community expedite the clinical application of these therapies for various diseases and conditions. Audience A broad range of researchers, scientists, and engineers in diverse fields such as materials science, biomedicine, biomedical engineering, biology, chemistry, physics, biotechnology, pharmacology, toxicology, and formulation scientists.
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Seitenzahl: 792
Veröffentlichungsjahr: 2023
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Table of Contents
Cover
Table of Contents
Series Page
Title Page
Copyright Page
Foreword
Preface
Acknowledgment
1 Biocompatible Hydrogels for Gene Therapy
1.1 Introduction
1.2 Hydrogels Classification
1.3 Fabrication of Hydrogels and Its Desirable Technical Features
1.4 Factors to be Tuned for Gene Encapsulation in Hydrogels
1.5 Recent Advances on Hydrogels for Gene Delivery
1.6 Conclusion
References
2 Use of Polysaccharides
2.1 Introduction
2.2 Cross-Linking Techniques for Engineering Polysaccharides-Based Biomaterials
2.3 Approaches to Design Polysaccharide-Derived Biomaterials
2.4 Biomedical Applications of Polysaccharide-Derived Biomaterials
2.5 Advanced Biomaterials for Wound Dressings
2.6 Scaffolds for Tissue Engineering and Development of Bioinks for 3D Bioprinting
2.7 Recent Utilization of Polysaccharides
2.8 Toxicity Concerns of Polysaccharide-Derived Biomaterials
2.9 Preclinical and Clinical Studies on Gene Delivery Using Polysaccharide-Based Biomaterials
2.10 Challenges and Future Directions
2.11 Future Prospects
2.12 Conclusion
References
3 Polysaccharide-Based Biomaterials for Gene Delivery
3.1 Background
3.2 Introduction
3.3 Gene Therapy
3.4 Gene Delivery Systems Based on Polysaccharides
3.5 Practical Application of Gene Delivery Systems
3.6 Polysaccharide-Based Nanoparticles
3.7 DNA Delivery
3.8 Conclusion
References
4 Hydrogel-Based Gene Therapy
4.1 Introduction
4.2 Gene Therapy
4.3
In Vivo
Gene Therapy Using Hydrogels
4.4 Encapsulating Cells in Hydrogels for Gene Therapy Delivery
4.5 Hydrogels for Integrative Tissue Engineering and Cell Delivery
4.6 Biocompatible Hydrogels for Transferring Cells
4.7 Using Hydrogels for Gene Therapy in Tissue Engineering-Based Drug
4.8 Human Gene Therapy that Uses Hydrogel as an Alternative Method of Delivering Genetic Material to Patients
4.9 Recent Advancement in Biocompatible Hydrogel
4.10 Applications of Hydrogel
4.11 Current Hydrogels in Clinical Trials
4.12 Conclusions
References
5 Progress and Prospects for Non-Viral Gene Therapy
5.1 Introduction
5.2 Definition
5.3 Technology Overview for Non-Viral Gene Delivery
5.4 Chemical Carriers for Gene Transfer: Establishing Effective
In Vivo
Gene Delivery
5.5 Types of Gene Delivery
5.6 Reduction of Immunological Responses Through Alteration of Delivery Method or DNA Structure
5.7 To Enable Long-Lasting Gene Expression, Self-Replicating, Tissue-Specific, and Integrating Plasmid Expression Systems are Designed
5.8 Hybrid Vector Systems to Improve Transfection and Lessen Cytotoxicity
5.9 Vehicle Material
5.10 Further Effects
5.11 Challenges and Prospects
5.12 Conclusion
References
6 Nanoparticles for Tumor Gene Therapy
6.1 Introduction
6.2 Technologies for Gene Delivery
6.3 Cancer Treatment with Gene Therapy
6.4 Gene Therapy Using Nanotechnology
6.5 Challenges and Future Aspects
References
7 Effective Gene Transfer with Non-Viral Vectors
7.1 Introduction
7.2 System Development for Delivering Genes
7.3 Methods for Non-Viral Vector for Delivery of Genes
7.4 Delivery System
7.5 Current Methods for Nonviral Gene Delivery: Benefits and Drawbacks
7.6 Current Barriers for Non-Viral Vectors
7.7 Possibilities for Enhancing the Non-Viral Vector Delivery System
7.8 Conclusion
7.9 Future Relevance
References
8 Utilization of Chitosan for Gene Delivery
8.1 Introduction
8.2 Cationic Polymers-Based Gene Delivery Systems
8.3 Chitosan and Its Derivatives in Gene Delivery Systems
8.4 Chitosan as Chemotherapeutic Drugs
8.5 Conclusion
References
9 Nanoparticles as Gene Vectors in Tumor Therapy
9.1 Introduction
9.2 Polymer-Based Nanocarriers: Their Technology and Recent Advances
9.3 Conclusions
References
10 Progress in Non-Viral Delivery of Nucleic Acid
10.1 Introduction
10.2 Physical Methods of Non-Viral Nucleic Acid Delivery System
10.3 Advantages and Disadvantages of Physical Transfection
10.4 Chemical Methods of Non-Viral Nucleic Acid Delivery System
10.5 Advantages and Disadvantages of Chemical Transfection
10.6 Cellular Barriers for Nucleic Acid Delivery Faced by Non-Viral Vectors
10.7 Challenges and Limitations of Non-Viral Nucleic Acid Delivery System
10.8 Conclusion
References
11 The Junction of Biomaterials and Gene Therapy – Current Strategies and Future Directions
11.1 Introduction
11.2 Viral Gene Therapy
11.3 DNA Viral Vectors
11.4 Adeno-Associated Viral Vectors
11.5 Non-Viral Gene Therapy
11.6 Recent Advances in the Development of Gene Delivery Systems
11.7 Development of Gene Delivery Systems
11.8 Viral Vectors Based on DNA for Gene Delivery Systems
11.9 Viral Vectors Based on RNA for Gene Delivery Systems
11.10 Oncolytic Viral Vectors for Gene Delivery Systems
11.11 Practical Application of Gene Delivery Methods
11.12 Conclusion
References
12 Utilization of Silk for Gene Delivery
12.1 Introduction
12.2 Dimensional Structure of Silk
12.3 Properties of Silk
12.4 Extraction of Fibroin from Silk Worm
12.5 Fabrication of Silk in Different Therapeutics Carriers
12.6 Utilization of Silk for Gene Therapy
12.7 Properties of Silk Fibroin as Biomaterial
12.8 Summary of Silk-Based Formulations for Gene Delivery [33]
12.9 Examples of Some Delivery Approaches which Utilizes Silk as a Biomaterial for Gene Delivery
12.10 Some Highlights of Silk Fibroin
12.11 Conclusion
References
13 Challenges and Emerging Problems in Nanomedicine Mediated Gene Therapy
13.1 Introduction
13.2 Why Nanomedicine Over Traditional Drugs?
13.3 Nanomedicine for Gene Therapy
13.4 Complications in Nanomedicine-Mediated Gene Therapy
13.5 Challenges in the Clinical Translation of Nanomedicines
13.6 Conclusion
References
14 Biomaterials-Based Vaccination in Cancer Therapy
14.1 Introduction
14.2 Tumor-Associated Antigens
14.3 Vaccine Delivery
14.4 Dendritic Cells
14.5
In Vitro
Generation of Dendritic Cells
14.6 Usage of RNA
14.7 RNA-Pulsed DCs as Vaccines
14.8 RNA Vaccines
14.9 Optimization of Immunotherapy
14.10 Cancer Treatment Through RNA Interference
14.11 Conclusion
References
Index
End User License Agreement
List of Tables
Chapter 2
Table 2.1 List of patents on polysaccharides-based biomaterials for gene deliv...
Chapter 3
Table 3.1 Nanoparticle drug carriers based on polysaccharides and their classi...
Chapter 4
Table 4.1 Controlled delivery of gene vector: Hydrogel [73, 74].
Table 4.2 Therapeutic applications of parenteral hydrogels categorized by mate...
Table 4.3 List of ongoing injection based hydrogel in clinical trials [100–103...
Chapter 6
Table 6.1 Patents on suicide gene therapy for cancer.
Table 6.2 Nanoparticles used for gene delivery in cancer therapy.
Chapter 10
Table 10.1 Immune response generated against viral vectors.
Table 10.2 Various non-viral vectors and their gene delivery target used in sp...
Chapter 11
Table 11.1 Types of non-viral gene delivery methods.
Table 11.2 Some commercially available biomaterial-based products [17].
Table 11.3 A broad comparison of viral and non-viral transfection vectors [18]...
Table 11.4 Some examples of mixed hydrogels for biomedical applications [19].
Chapter 13
Table 13.1 List of FDA-approved cellular and gene therapy products.
Table 13.2 Nanoparticles used in gene therapy.
List of Illustrations
Chapter 2
Figure 2.1 Chitosan.
Figure 2.2 Alginate.
Figure 2.3 Dextran.
Figure 2.4 Cellulose.
Figure 2.5 Advantages of polysaccharides-based biomaterials.
Figure 2.6 Reactions of polysaccharides.
Chapter 4
Figure 4.1 Properties of biocompatible hydrogel.
Figure 4.2 Classification of hydrogel.
Chapter 5
Figure 5.1 Different methods for injecting bare DNA and enhancing techniques.
Figure 5.2 Method of delivering non-viral gene vectors.
Figure 5.3 Vehicle materials.
Chapter 6
Figure 6.1 The strategies used for gene therapy: (a) By imparting a functional...
Figure 6.2 A summary of the gene therapy delivery methods [2].
Figure 6.3 Mechanism of internalization of the nonviral vector carrying into c...
Chapter 7
Figure 7.1 Systems for delivering genes. As part of the viral gene delivery me...
Figure 7.2 A nonviral method of gene delivery. It demonstrates the polymer, li...
Figure 7.3 Polymer based nanovector. When these cationic polymers combine with...
Figure 7.4 Lipid based nano-vectors. Liposomes are specialized types of nanopa...
Chapter 9
Figure 9.1 Polymeric materials used for gene delivery purposes towards cancer ...
Figure 9.2 Advantages and limitations of non-viral polymer-based gene delivery...
Figure 9.3 Chimeric EWS-FLI1 gene product siEFBP2 siRNA non-viral encapsulatio...
Figure 9.4 DMP cationic micelles used as non-vectors for suicide gene therapy ...
Figure 9.5 Molecular structures of lipids used in gene therapy formulations an...
Figure 9.6 Schematic representation of AuNPs multifunctionality.
Chapter 10
Figure 10.1 Types of nucleic acid used for transfection.
Figure 10.2 Physical and chemical methods of non-viral nucleic acid delivery.
Figure 10.3 Intracellular and extracellular barriers for nucleic acid delivery...
Chapter 11
Figure 11.1 A diagram depicts both
in vivo
and
ex vivo
gene therapy.
In vivo
g...
Figure 11.2 Clinical trials for gene therapy use many vectors [2].
Chapter 12
Figure 12.1 Dimensional structure of silk [3].
Figure 12.2 Different properties of silk.
Figure 12.3 Steps of fibroin formation.
Chapter 13
Figure 13.1 Viral and non-viral vectors used in nano-medicine mediated gene th...
Figure 13.2 Schematic illustration of nanomaterial mediated gene delivery show...
Figure 13.3 Challenges associated with the NM-mediated gene therapy.
Chapter 14
Figure 14.1 Overview of RNA-vaccination strategies employing DCs (a) and pure/...
Figure 14.2 The technique for adopting cancer-specific customized medications ...
Guide
Cover Page
Series Page
Title Page
Copyright Page
Foreword
Preface
Acknowledgment
Table of Contents
Begin Reading
Index
Wiley End User License Agreement
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Scrivener Publishing100 Cummings Center, Suite 541JBeverly, MA 01915-6106
Publishers at ScrivenerMartin Scrivener ([email protected])Phillip Carmical ([email protected])
Integration of Biomaterials for Gene Therapy
Edited by
Rishabha MalviyaSonali Sundram
and
Neelam Jain
This edition first published 2023 by John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA and Scrivener Publishing LLC, 100 Cummings Center, Suite 541J, Beverly, MA 01915, USA© 2023 Scrivener Publishing LLCFor more information about Scrivener publications please visit www.scrivenerpublishing.com.
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Library of Congress Cataloging-in-Publication Data
ISBN 978-1-394-17473-7
Cover image: Pixabay.ComCover design by Russell Richardson
Foreword
It gives me immense pleasure to write the foreword for this book edited by Dr. Rishabha Malviya. He is well-known and dignified in the pharmacy field, and his research has an excellent reputation. The quality of his work is always impressive, and this time is no exception.
Gene and cell therapies are seeing a resurgence, with an acceleration in scientific innovation and renewed interest in how they should benefit society. The book Integration of Biomaterials for Gene Therapy will enhance our understanding of biomaterial's functionality in gene therapy, which is a promising treatment option for many diseases such as cancer, inherited disorders, and certain viral infections. Scientists who are involved in drug delivery targeting will find this book to be a useful resource, because it provides essential information about a key biomaterial-integrated gene therapy, discusses how biomaterials can assist in targeted gene treatment, and brings together professionals in the field to explain the optimization, development, and integration of biomaterials for gene therapy. Moreover, this book emphasizes bio-based materials that have been used already in potential applications of biotherapy, including gene delivery, immunotherapy, stem-cell therapy, and tissue engineering.
In this book, various international professionals present a broad view of the subject, and the subsequent efforts of its readers will enhance the effectiveness of biomaterial-based delivery. I truly appreciate the time and effort that the authors have invested in this project. I believe that each one has taken extra pains to complete this book, paying great attention to its quality and timeliness.
Dr. Ramchander Khatri
Asst. Controller of Examination Delhi Pharmaceutical Sciences and Research University, (Govt. of NCT of Delhi), New Delhi, India
Preface
Many organic and inorganic, synthetic, or naturally sourced materials are considered usable in biomedical and pharmaceutical sciences because they are not toxic to humans. These materials are commonly referred to as biomaterials because they can be introduced into living human tissues for prostheses, as well as for drug delivery, diagnosis, treatments, tissue regeneration, and a variety of other clinical applications. For a while now, nanoparticles and bioabsorbable polymers have substantially expanded the fields of application of biomaterials, gaining much greater attention from the biomedical world. The development of biomaterials and their production are not new concepts in science and research. More recently, biomaterials have been employed to deliver genes in a more programmable, controlled, and targeted manner. Unfortunately, despite recent developments, there has been little success in transferring innovative medication and gene delivery systems to the clinical practice. Consequently, the need to close gaps in the translational application of biomaterial-based drug and gene delivery systems is urgent. Results can be improved and made more efficient by having a thorough understanding of the nature, characteristics, properties (physical, chemical, and mechanical), and biological performance of the various biomaterials. To address the need, this book covers biomaterials-mediated gene delivery utilizing gene vectors and the fundamental facts about biomaterials, including various biological and engineering challenges.
This book comprises research and review articles from leading researchers with multidisciplinary experience. It discusses many broad topics, including nanoparticle-enabled gene therapy, inorganic nanocarrier-based gene delivery, non-viral delivery of nucleic acid, biocompatible hydrogels, silk, and polysaccharides-based gene delivery. Other gene delivery topics discussed include the use of smart and engineered biomaterials, combined therapy with growth factors and cell transportation, and the prospects and challenges in the treatment of different diseases, including cancer.
The book bridges the knowledge of pharmaceutics, engineering, basic sciences, and clinical research fields in a way that will help the research community to expedite the clinical application of these therapies for various diseases and conditions.
The Editors
Acknowledgment
“Trust in the lord with all your heart and lean not on your understanding; in all your ways submit to him, and he will make your path straight”
First, I would like to thank God Almighty for giving me the life, opportunity, and guidance to achieve my goals and be successful. I am deeply indebted to Galgotias University which has allowed me to rise as a researcher and provided continuous motivation and support. Thank you for believing in me.
A few people have helped to make this book successful, and I am very grateful to all. I extend very special thanks to my friends who deserve special acknowledgment and thanks.
I could not have undertaken this journey without the support of my family. Their endless love and encouragement make possible the completion of all my tasks. Words cannot express my gratitude towards them.
As the principal editor of this book, I wish to express my sincere gratitude to the prestigious Wiley-Scrivener Publishing imprint for their excellent services. I have especially enjoyed my scholarly work with Scrivener as they have been timely, creative, and very helpful on my previous books with them.
Rishabha Malviya
1Biocompatible Hydrogels for Gene Therapy: Advancement and Applications
Ankita Gupta1 and Swatantra K.S. Kushwaha2*
1 Department of Pharmaceutics, Bombay College of Pharmacy, Mumbai, India
2 Krishna Institute of Pharmacy and Sciences, Kanpur, India
Abstract
Gene therapy is gaining researchers interest to be a beneficial armamentarium in the treatment of various acquired and inherited diseases. Hydrogels carry the good potential to modify present gene therapy due to their superior biocompatibility, capability to mimic an environment that supports new cells and tissue growth, and regulate gene delivery to promote differentiation and improve therapeutic after effects. Hydrogel can also be integrated with genes to initiate differentiation for tissue regeneration. An emerging promising strategy is to design hydrogel for dual cell and genetic material distribution utilized to engineer the bones and tissue to stem cell differentiation down the chondrogenic lineage to produce cartilage. Hydrogel-based delivery of genes was also investigated for the repair of cardiac tissue and coding of Plasmid DNA. Hydrogel bio-materials can overcome barriers to gene therapy by meticulously regulating the expression of transgene vectors. The limitations include preventing genotoxicity arising from integrated vectors for gene delivery, regulating genome off targeting, increasing transfer efficacy of genes to a level effective for cure of ailments, reducing the body’s defenses generated by vectors administered in-vivo, moving to common consent for dealing with concerns like justified germline editing. The emerging scope of hydrogel for gene therapy, and its multi-variant aids for the well-being of living beings, as studied via technical innovations along with scientific accomplishments across earlier numerous ages, supports continual hopefulness along with escalating hard work for formulating the delivery system best amongst treatment of serious diseases.
Keywords: Hydrogel, gene therapy, natural polymer, tissue engineering, vectors, PEG, VEGF, plasmid DNA
1.1 Introduction
The material of engrossment in this chapter is on hydrogel for gene therapy. Hydrogels are a 3D network formed by cross-linking of hydrophilic polymers that can imbibe huge amounts of water and biological fluids thereby maintaining its structure. Its implicit biocompatibility and physical properties resembling natural tissue make it apt for a myriad of in vivo applications. Recent applications for hydrogel are in the areas of gene therapy, therapeutic delivery, tissue repair & engineering, wound repair, bio-sensors elements, pH sensitivity and as diagnostics tools.
Gene delivery through hydrogel is investigated to be an interesting tool for multiple clinical applications; a few are regenerative medicine, inherited disorders treatment via gene therapy and drug delivery. The large water imbibing capability and least reactive synthetic features of hydrogel makes it apt for delivery of gene by preserving lentiviral vectors activity and protect it from host immune response. Hydrogels are also designed for use in restoration of tissues as three dimensional bio-printed structures [1], injectable [2], stimuli-responsive, or adhesive systems [3].
Gene delivery can be utilized for short-term as well as extended transgene presentation at particular location, resulting in local or systemic effects. It can be also utilized by altering gene sequence or for multiple gene delivery escaping re-fabrication of delivery system. This flexibility aids its increase utilization for biomaterialgene delivery technique yield the most therapeutic benefit. The impeding factors to be addressed are virus activity, dose, immune response generated by the host. Biomaterial platforms could be one of the methods to address above limitation encouraging stability of vector and also protecting form host immune system. Hydrogel also investigated by researchers for tissue engineering, it encourages permeation of cells, also drive to encapsulate vectors that code for elements that aids development of tissues. Sustained and localized expression of lentiviral vector at implantation site can be achieved by the hydrogel delivery tool.
The tunable structure of hydrogel assists to regulate it swelling and degradation which is leveraged to drive gene therapies as well as regulate behavior of transplanted cells. Entrapment and modification of vectors within hydrogels restricts its elimination through defense mechanism of humans. Hydrogels can also be fabricated for onsite delivery or get biologically stimulated, drive penetration of stem cells, cartilage cells, etc. and to develop tissues and bones. Hydrogel can be synthesized by either cross-linking as well as self-arrangement of hydrophilic man made or organic polymer like chitosan, dextran, cellulose, poly (N-isopropyl acryl amide), polyurethane respectively.
It’s a challenging task, though, to control the properties of hydrogel in the complex tissue environment of healthy and diseased cells. Moreover, it is also adorned using bio-similar characteristics to assist binding and transfer of specialized cells, resulting in increased ability of cells to undergo transduction. In contrast to other biomaterial delivery systems, hydrogels provide a hydrated, less reactive, aqueous synthetic environment that assist in entrapment of gene vectors. Hydrogel might be utilized for several therapies. For example, it might be used to deliver vectors for gene technologies, and may improvise functions of cells being transplanted, hydrogels intended for VEGF is also investigated to cause neo-vessel development in addition to inhibit thrombosis in stent.
Hydrogel are also adorned to initiate interactions among chemicals and lentiviral vectors resulting in successful retention or release of vector in gel assisting distribution of transduced cells. Hydrogel cell infiltration rate is also found to influence location as well as the extent of transgene expression. Significant research has been conducted in the design, optimization, and applications of hydrogels for therapeutic purpose. But still its large-scale manufacturing has not been achieved due to lack of novel materials, low efficiency in technical terms for bulk production of hydrogels, and scope to formulate scaffolds containing biologically active macromolecules. The goal for this chapter is to publish study report on cutting-edge research work on development and applications of hydrogels with major emphasis on its use as gene delivery.
1.2 Hydrogels Classification
Depending on source of polymer: It can be synthesized by either natural/synthetic polymers.
Depending on composition of polymer:
Homo-polymeric: Single species of monomer is used to develop polymer network.
Co-polymeric: Polymeric network chains consist of alternate arrangement of different monomers with hydrophilic component.
Multiplier: Twining of cross-linked and non-cross-linked polymer in a network.
Depending on configuration
Amorphous, Crystalline, and Semi crystalline Polymers
Depending on physical appearance
Depending on polymerization technique hydrogels can be classified to occur in form of Films, Matrix or spheres.
Depending on E-charge they posses
Depending on charge be present on polymer chains it can classified as Nonionic, Ionic, Amphoteric or Zwitter ion.
1.3 Fabrication of Hydrogels and Its Desirable Technical Features
Hydrogels can be developed by self-assembly process or by cross-linking of polymers of hydrophilic nature to form a web like system [4]. Its spongy as well as hydrous morphology result in formation of gels and aids in swelling in living micro-environment, that eases it localized administration through injection without any invasive surgery. A hydrogel synthesized by following methods:
Physical approach: It includes hydrogen bonding/ionic/hydrophobic interaction.
Chemical approach: It includes photo-polymerization or cross-linking pathway.
The core technical features of an ideal hydrogel include:
The high capacity of absorption in saline.
Type of application influences expected rate of absorption (particle size and porosity).
High under load absorbency.
Low content of soluble matter and residue matter.
Good stability during storage.
Biodegradable.
Maintain normal pH after swelling also.
Photo stability, Colorless, odorless, and inert.
1.4 Factors to be Tuned for Gene Encapsulation in Hydrogels
Diffusion of vector hydrogel is depended on various parameters such as amount of pores present, hydrophobic or hydrophilic, degradation mechanism and interaction rate of material with vector. Virus retention ability and the capability of cells to infiltrate hydrogels are major factors influencing transgene expression. Polymers of natural origin are preferred owing to good bio-compatibility as well as its intrinsic ability of natural connections with cells that influence addition with cells along with its differentiation. Whereas polymers of synthetic origin have ability to fabricate hydrogels with precisely controlled physical characteristics such as its degradation, influencing development of tissues along with transfer of genes. It also can modify duration and extent of presentation of transgene at grafted location as compared to bolus injection.
The delivery efficiency of gene is dependent on combined effects of activity of vector and efficiency of hydrogel on host response. Sustained release is obtained by vectors entrapped within hydrogels. It aids in keeping high vector concentrations at local site of administration resulting in cellular infiltration. Hydrogel synthesized using natural or synthetic polymers can be prepared under mild conditions and therefore are better for entrapping gene therapy vectors without influencing activity of vectors.
Mesh size of hydrogels are one of the important factor influencing release or retention of vector. If the mesh size is more than the diameter of vector then the release is rapid with diffusion whereas if vector diameter is more than mesh size then the release rate depends on hydrogel degradation rate. Smart hydrogels that are formed by stimuli sensitive polymers, variation in there pore size occurs on stimulation and are excellent in controlling vector release.
Interactions among hydrogels and vector also prevent vector diffusion away from hydrogel resulting in increased localized concentration of vector and thereby aids effective gene transfer. Linkage of vectors with biological substrate also aids attachment of cells of and can also retain virus and cell for efficient gene transfer. Hydrogel prepared from cationic polymers, poly ethyelene glycol adorned with peptides with cationic and chitosans are utilized to enhance retaining of vectors. Lentiviral capsid proteins are modified to Co-bind with components of fibrin at time of development of polymers and deliver vector via degradation of hydrogels.
Optimization of interaction strength between vector and hydrogels must be done such that it must be not too strong to prevent release of vector to prevent its internalization and interaction by nearby cells nor too weak to inhibit vector retention. Rate of distribution is adjusted to maintain 3D retention of gene vectors. Maximum infection level has been observed with lentivirus encapsulated in low-medium fibrin concentration, whereas vector diffusion rate was found to be inefficient at high fibrin concentration.
While above searches reveal the budding efficacy of hydrogels centered on natural polymers for localized gene delivery, synthetic hydrogels are utilized to meticulously control mode and dynamics of cell infiltration as well as degradation rate of hydrogels. Such as, PEG hydrogels cross-linked by protease-sensitive peptides. On movement of cells via hydrogels, degradation of crosslinks permit synchronized permeation of cells along with delivery of gene. Utilization of manmade gels similarly permit addendum of specialized and protease-susceptible peptides that favorably influence infection of specific cell type.
For facilitating robust cell-infiltration, synthetic hydrogels are integrated with interconnected macropores utilizing diverse approaches. Amending size of macropores along with density can regulate cell infiltration in parallel of degradation as well as vector release of hydrogels. Hydrogels also fabricated to foster permeation and transfer of genetic material of specific cell types through integrating short biologically active peptide obtained by extra-cellular medium like RGD peptides to scaffoldings. Regarding gels based on synthetic polymers, the meticulous regulation of adhesive sites densities is utilized to modify potency of biomaterial supporting cell growth and attachment and types of receptor in extra cellular cells which facilitate above connections.
Speed of matrix degradation which transforms movement of cell via matrix impacts combination with tissue of the host. Incorporation with bio compatible material designed towards current precise signs like spatial, mechanical, and chemical as well as gene therapy vectors embodies an encouraging approach to foster development and restoration of tissues.
1.5 Recent Advances on Hydrogels for Gene Delivery
Hydrogels are utilized as regenerative medicine because of its capability to develop an environment that aids transplanted or endogenic permeating cells that facilitate them to recondition the purpose of tissue vanished because of ailment. Moreover, it can be used like transportation tool for medicinal genes that guide and augment the role of relocated or endogenic cells. Some of the latest advancements are discussed in this section.
Lee et al. [5] fabricated a chitosan based thermo-responsive hydrogels for gene therapy to enrich the local transgene expression. Photo-irradiation approach was utilized for chemical cross-linking. The duration of photo-irradiation as well as content of chitosan was found to regulate rate of release of plasmid DNA incorporated in hydrogel.
Gene therapy could be used to aid dermal recurring injuries exhibiting transformed expression of genetic material and de-regulation of mRNA. Though, it is challenging to carry extended and controlled delivery of therapeutics due to its irregular topology.
Jose and Researchers designed a model for dressing of lesion centered upon viscous and elastic hydrogels prepared of polyβ-amino esters and polymers made of polyethylene glycol. It was attested to be decomposable, cell-compatible, and first and foremost, injectable. The later features endorsed it to be used in-situ gel form that can be easily applied to irregular, deep wounds like chronic ulcers [6].
Ravishankar et al. utilized chitosan and lignin to develop biocompatible hydrogel. High firmness as well as viscous nature of chitosan was found to be enhanced on integration of lignin. In vitro studies reported hydrogels to be benign to mesenchymal stem cells and also in-vivo assay it was found to be nontoxic to zebra fish at concentration of 10 mg/mL [7].
Lei et al. [8] displayed utilization of fibrin hydrogels for competent, cell-controlled, and 3D retained gene transfer to targeted cells. Researchers studied fibrin-facilitated gene transfer via incorporating plasmid DNA inside hydrogels matrix through polymerization as well as utilized dual approaches for gene transfection and cells, retained outside or inside hydrogel. Retention of target cells along with lipoplexes inside hydrogels granted better gene transfer efficacy compared to cells seeded on outside surface of gel. Fibrin hydrogels amended transport of genes via reducing toxicity effects on cells of transaction mediators like lipofectamine.
In conventional gene transfer approach target cells were exposed to large content of lipoplexes promptly, although in case of fibrin related hydrogels, cells for gene delivery were bared with exposed to lipoplexes steadily degrading the hydrogel. Its steady contact with cell damaging mediators mitigated stimulation of pro-apoptotic pathways thus reduced necrosis and apoptosis of cells.
Cyclodextrin depended supramolecular hydrogels comprising cationic polymers also displayed reduced cell toxicity along with effectual transfection in genes in cell cultivations. Prime characteristics in developed matrix are that polyplexes linked to DNA and any polymer can be reformed via formation of complex because of high proportion of cyclodextrin [9, 10]. Pegylation of PEO-adamantane via arrangement of complex connecting adamantane to β-cyclodextrinon complex of polymers with DNA can be observed for stabilizing polyplex nanoparticles, resulting in better transfection in genes.
Polyethylene glycol related photo-cross-linked gels for delivery of gene in sustained mode, got explored with the experiment of Anseth researchers. Polymer matrix was developed by poly ethylene glycols, which were core fastened to poly lactic acid and poly caprolactone block to encourage degradation, and adorned using meth-acrylate moieties that promote its fast photo-polymerization. Release from pDNA was modified for several days, having straight arrangement devoid of the preliminary sudden release through amending variety and configuration of polyester.
Nikolaev et al. [11] fabricated PCL along with fibrin containing system of hydrogel providing on site release of plasmids holding genes coding for vascular endothelial and fibroblast growth factor, rooted inside sciatic nerve of rat having nerve diastasis. On site jab of plasmid at place of traumatic wound promoted restoration at sciatic nerve of rat along with functions of motor and sensory nerves retrieved.
In spite of great potential of hydrogels, its usage is at initial stage for delivering gene in a controlled manner to repair cartilage. Osteochondral and chondral components can be particularly hopeful to deliver the polymeric gene because of limited flow of blood at the site which worsens transfer of DNA. Gonzalez-Fernandez et al. [12] displayed spatial porous bioinks which offer a momentary 3D transfer of gene via moderating the porous features. Hydrogels derived from MC-Alginate were stacked by osteogenic, chondrogenic and SOX9 genes to yield automatically supported, scaffolding by activation of genes. Resultant mode of gene delivery, in vitro stimulated osteogenesis and chondrogenesis in mesenchymal stem cells. On implantation inside cells, 3D printed bioinks fabricates reinforced advancement of bony tissues with new blood vessels laden with cartilage layer.
Wegman and group [13] experimented efficacy for development of bones via means of hydrogel derived from alginates. GAMs compared to plasmid DNA-GAMs, resulted in improved production of cartilage and muscle packed with plasmid DNAs encoding for osteogenic factors. It was merged to specialized markers in vitro. On transfection of cells with above system resulted in expression of genes for more than 2 weeks.
Spinal cord injuries frequently directed to dysfunction of nervous system because of malfunctioning in re-development of axon. Fabrication of spatial nanofibrous hydrogels scaffoldings as biostimulated and biocompatible media that offer extended delivery of genes and contact guidance, demonstrated to be appealing methodology aimed at healing of neurological wounds. Nguyen et al., [14] developed spatial hydrogels derived from collagen embedded with Poly-e-caprolactone polymers co-polymerized to ethyene phosphate via electron spinning techniques to release protein like neutrotrophins and micro RNA in vivo.
1.6 Conclusion
Hydrogels carry vast prospects to improvise existing technology for gene delivery and have a firm effect on gene therapy technologies as well as regenerative medicine. Contrary to injecting a bare lentivirus, its entrapment inside gels or synthetic amendment using polymers enhance in vivo retention as well as inhibit deactivation of a vector through the body’s defense mechanism. In addition to this, it can retain localized, elevated concentration of vector that surmounts bulk movement restrictions for gene delivery.
Furthermore, it also displays peptide motifs which encourage adhesion of cells and retention of vectors. This approach increases co-localization of target cells and vectors, thus stimulating gene transfer. It also has immense possibility for various gene as well as reformative therapies. It increases capacity for lentiviral vector therapy via restricting it to localized tissues, protecting scavenging the immune system along with increased efficacy of transduction. In case of restoration therapy medicine as well as gene engineering purposes, hydrogels are also modified for rendering cell adhesion, bio-degradable characteristics which imitate relevant tissues in vivo.
Hydrogel possesses extended prospect to regulate transgene expression at various levels, time span and specific targets, which majorly blocks successful delivery of gene. Entrapment of gene vectors in gels or hydrogel reformation protects deactivation of a vector via the host defense mechanism. Moreover, it is tailored by bio imitating properties that support connection and movement of specialized cells, to enhance transduction in cells. Structure of gel dependent gene therapy for reformation treatment must maintain equilibrium between the reduced immune response and control vector clearance during the increment of cell permeation.
Gene vectors entrapped inside hydrogels which formulate for controlling activation of immune cells possess restricted delivery of gene, that arise by less recruitment of cells because of reduced cell-template connections specific for them which regulate stimulation of cells in the immune system. In reformative treatment, this is developed for promotion of cellular processes related to development of tissues, and release of vectors results in enhanced bioactivation.
Effectual transfer of genes exhibit an equilibrium in vector retaining against its release from hydrogels, the vector steadiness and speed of permeation in cell inside system. Several prospects persist for more enhancing hydrogel characteristics, emerging tools to enhance cell transduction along with offering multidimensional and sequential restriction on the expression of genes which simulate complicated models of gene expression existing in tissue growth. It offers an exclusive means which is engineered to coordinate with necessities for effective gene delivery and fostering tissue formation.
To conclude, hydrogels for gene transfer correspond to a hopefully budding scope for exploration of forthcoming efficient as well as secure medication of a plethora of ailments. Above reviewed approach assists by-pass existing restraints in gene remedy, they are also modifiable as bespoke for restoration of tissues.
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Note
*
Corresponding author
:
2Use of Polysaccharides: Novel Delivery System for Genetic Material
Prashant Kumar1, Swatantra K.S. Kushwaha2*, Neelottama Kushwaha2, Abhishek Singh1 and Surya Nath Pandey1
1 Teerthanker Mahaveer College of Pharmacy, Teerthanker Mahaveer University, Moradabad, Uttar Pradesh, India
2 Krishna Institute of Pharmacy and Science, Kanpur, Uttar Pradesh, India
Abstract
Due to their biocompatibility, biodegradability, and distinctive bioactive features, polysaccharides have been identified as attractive candidates for a variety of biological applications in gene therapy and tissue engineering. Gene delivery is a method to relocate external DNA into the presenter cells for genetic research or gene remedy of human hereditary disorders. Gene therapy is one of the promising therapies for the management of various diseases like cancers; Alzheimer’s viral infection as well as inherited diseases polysaccharides (carbohydrates) is usually isolated from plants and animal sources abundant in nature. For the delivery of genes, many polysaccharide-based biomaterials are being researched, including starch, cellulose, chitosan, dextran, and alginates. Further, these polymers are widely accepted by the body due to their biochemical similarity with human extracellular matrix components regulating cell signaling and tissue growth. Further, polysaccharides-based biomaterials are designed as graphene, metal oxide, and carbon nanotubes utilized in diverse fields of research. Recently, the major focus of research has been concentrating on the identification of the efficient and safe substitutes for the viral vehicles required in gene delivery. Future research can be expected to face significant hurdles related to understanding the molecular interactions of interacting compounds, the destiny of polysaccharide nanoparticles in vivo, and the molecular interactions between polysaccharides and loaded drugs/genes. The current chapter is primarily concerned with an overview of polysaccharide-based biomaterials for a variety of biomedical applications, including gene transfer. Additionally, the focus will be on structure, cross-linking mechanisms, biosynthesis, chemical characteristics, biological properties, current problems, clinical usage, recent advancements, and methods to build polysaccharide-derived biomaterials. Finally, numerous future prospects for the design and fabrication of polysaccharides-based materials to accomplish their extensive commercial usage are discussed.
Keywords: Polysaccharides, bioactive, gene delivery, clinical trials, biodegradable, tissue engineering
2.1 Introduction
Polysaccharides are an essential class of biopolymers with decent biocompatibility, easy accessibility, biological acceptability, and prototypes for structural modifications. Polysaccharides derived from natural sources offer antibacterial, antiviral, and anti-inflammatory potential, and they own outstanding biocompatibility. As a result, they have received a lot of attention as efficient biomaterials for use in biomedical applications. As regenerative therapies and drug delivery systems, engineered carbohydrate-based biomaterials offer an alternative. These include cellulose, dextran, hyaluronic acid, chitosan, and other polysaccharides originating from plants or animals. These are the most widely used sources of biopolymers because they can be used to create composites, films, sheets, hydrogels, fibers and composites for the features including tissue engineering, medication delivery systems, and wound healing [1, 2]. Polysaccharides have a wide range of uses, including food, pharmaceutical carriers, biomaterials, hydrogels, food stabilizers/thickeners, biosorbents, and enclosing agents. Monosaccharides naturally polymerize in specific patterns or sequences that are appropriate for each one’s function or involvement in the production of polysaccharides. By adding additional functional group(s), certain polysaccharides are further modified, giving rise to unique characteristics [3, 4].
Due to their advantageous properties of low immunogenicity, biodegradability, biocompatibility, and natural abundance, natural polysaccharides have drawn considerable interest in the development of microcarriers and nanocarriers. In this chapter, the most recent developments in gene delivery using natural polysaccharide-based micro- and nanocarriers are explored. Further, on the micro- or nanoscale, polysaccharides are used to create biomaterials and formulations [5].
Gene delivery has been hailed as a potent method for treating both acquired diseases such as multigenetic disorders and those brought on by invading virus genes as well as many inherited diseases [6, 7].
A number of techniques are used by gene delivery systems to aid in the absorption of the chosen gene by the cell. Building a gene delivery system necessitates a thorough study of the relationship between the delivery method and the target cell. It’s important to comprehend intercellular traffic and targeting mechanisms in order to develop more effective gene delivery techniques. It is the most popular gene via endocytosis, particularly facilitating cellular uptake of non-viral gene delivery [8, 9].
Cellular release occurs to start DNA transcription and translation as well as the production of the associated protein after the delivery system has been taken up by the cell through endocytosis. In order to enhance gene activity, a successful gene delivery process must reduce the possibility of an inhibiting the inflammatory reaction while also getting past certain obstacles at each stage. Viral gene delivery systems are made up of viruses that have underwent engineering towards becoming replication-deficient. These viruses are able to carry the genes to cells for expression. For the delivery of viral genes, lentiviruses, retroviruses, and adenoviruses are utilized [10–12].
The mechanism for delivering genes is a crucial technological element that is required for both fundamental study and therapeutic gene therapy. The use of polymer-based carriers have received a lot of interest since they are simpler to prepare and less harmful than viral carriers [13, 14]. However, there are still issues like toxicity spurred on by excessive contact between cationic gene transporters and the cytoplasmic membrane and reduced gene expression than viral carriers. For efficient gene expression, it is important to regulate nuclear entrance, endosome disruption, and cellular uptake of the polycation/pDNA complex. Moreover, gene delivery through polysaccharides methods such cationic dextran, cationic pullulan, chitosan, and chizophyllan18 have been created thus far due of their low toxicity and great biocompatibility [15].
2.1.1 Commonly Available Polysaccharide-Based Natural Biomaterials with Their Physicochemical Properties
Chitosan
Chitosan is thought to be the second most common natural polysaccharide on the market, behind cellulose. For 50,000–800,000 Daltons, chitin, and chitosan have been the main subject of study for several researchers [16].
Natural sources of chitosan include certain fungus like Mucor, Rhizopus, and Absidia. Chitosan is primarily a deacetylated derivative of chitin. Generally speaking, chemical and enzymatic methods are used to extract chitosan [17].
The natural polysaccharide chitin has a significant derivative called chitosan (CS). It is a naturally occurring, biocompatible cationic polysaccharide that contains amino acids. Because it contains amino groups, chitosan is simple to chemically alter. The capacity of CS-based DDSs to cling to negatively charged cell membranes, which is favorable to cell endocytosis, results in minimal immunogenicity and immunogenicity [18, 19].
The arrangement of various sugar molecules is evident in chitosan’s structure. Due to its special attributes to be biocompatible, biodegradable, and nontoxic, chitosan has become crucially significant in biomedical applications [20]. Numerous factors, comprising crystallinity, molecular weight, degree of deacetylation, etc., have a substantial impact on the physicochemical properties of chitosan. It is soluble in weak acids but insoluble in water and in alkaline conditions [21].
It has been established that chitosan-based biomaterials possess analgesic, antibacterial, antifungal, and mucoadhesive characteristics. These features are crucial and extremely valuable in tissue engineering and medication delivery applications. A major drawback to the use of chitosan in biological applications has been its solubility issue. The issue has so far been consistently addressed by numerous researchers through chemical modifications [22]. Additionally, the functional groups present in it might be chemically changed due to the development of carrier systems with good potential for transdermal, ocular, oral and nasal administrations [23]. Particularly, the production of chitosan (Figure 2.1) nanoparticles and their physicochemical conformation (such as concentration of protein and chitosan, deacetylation level and molecular weight) influence their potential to improve mucoadhesive property and facilitate drug/gene administration [24].
Figure 2.1 Chitosan.
Alginate
The main source of alginic acid is found inside the cell walls of common brown algae. Because of their peculiar egg-box shape and other chemical properties, gels can easily be created in aqueous media. Alginate can produce hydrogel through intramolecular and intermolecular cross-linking with divalent metal ions (Ca2+, Cu2+, Zn2+, Pb2+, etc.) in aqueous solution [25, 26]. Alginate (C6H8O6) n is an anionic based block co-copolymer composed of mannuronic and L-guluronic acids, with the M/G ratios vary depending on the sources. It is a linear, unbranched polymer [27].
Alginate is a polysaccharide that is called as frequently experience bioerosion, an extraordinarily gradual development that occurs in the microenvironment of a body and is also enzyme mediated, like many other polysaccharides. This is crucial to keep in mind when creating scaffolds as it facilitates tissue engineering and provides cells with a simpler way to get nutrients, the disposal of metabolic waste, appropriate oxygen, and more room to develop. Alginate solutions are insoluble in organic solvents and slightly more viscous in acidic environments. Their solubility in water depends on the solvent’s pH, the presence of free metal cations, and the medium’s ionic strength. Since alginate has so many different applications, numerous research teams have thoroughly examined the chemical changes applied to it. Using this polysaccharide, it is feasible to successfully produce enzymes, alkyl chains, hydrophobic polymers, amino acids and other functions by utilizing the carboxylic groups (-COOH) and cis diols contained in the alginate monomers [28–30].
Because of their biocompatibility, cross-linking activity, and gelling properties, alginate-based biomaterials and nanofibers are employed in the tissue engineering such wound dressing and drug delivery systems. The four most popular procedures for creating alginate nanoparticles include reverse microemulsion, decarboxylation, cross-linking, and evaporation [31–34]. Alginate salts that are water soluble are changed into water-insoluble salts by incorporating divalent groups (calcium, strontium as well barium), which cause the ionic cross-linkage between residues [35]. The cross-linked gel is created by electrostatic contact involving carboxyl groups and divalent ions. This phenomenon has a considerable impact on medication release. Owing to the anionic nature of alginate it can interact with cationic components. Because it contains positively charged medicines and molecules, it can be used to prepare delivery systems. The most often employed alginate based matrix for the development of drug- and gene-delivery systems is calcium alginate [36, 37].
Chitosan-coated alginate gel beads can be stored and circulated in vivo to extend the residence period. Additionally, compared to alginate or chitosan separately, alginate-chitosan polymeric complex was demonstrated to be a promising approach for the regulated release of integrated compounds. Additionally, isoniazid, pyrazinamide, ethambutol, and rifampicin’s bioavailability has been improved with the use of alginate (Figure 2.2) nanoparticles [38–40].
Dextran
Dextran, commonly referred to as glucan, is a starch-like water-soluble polysaccharide complex. It is frequently used as an adjunctive therapy for conditions like hemorrhagic shock and thrombus. Dextran is innocuous to living things and has excellent hydrophilicity and water solubility. Dextran’s molecular chain has several hydroxyl groups, making chemical modification easy [41].
By using such carriers, medications can be released under regulated conditions without being inactivated by bodily fluids or enzymes. In the presence of dextranse, the poly(DL-lactide co-glycolide), modified dextran with PLGA grafts core-shell-structured carrier demonstrated a rapid drug release rate [42, 43].
Figure 2.2 Alginate.
Lactic acid bacteria use sugar as a source to create the extracellular bacterial polymer dextran. Dextran, a homopolymer polysaccharide with the unit formula C18H32O16, is composed of glycosidic links with lengths ranging from 3 to 2000 kDa, which combined form linear chains and branches, respectively. The microbial strains and extraction technique have an impact on the physicochemical characteristics of dextran. Dextran is easily dissolved in distilled water and a few solvents, including formamide, glycerol, methyl sulphide, and ethylene glycol [44]. Dextran-based polymers have a variety of applications in the food business, cosmetics industry, wastewater treatment industry, and biomedical applications because of their biocompatibility, water holding capacity, low toxicity, and biodegradability [45]. The structure of dextran, which is similar to many other polysaccharides, is essential to understanding how it performs various tasks. Dextran’s characteristics are significantly influenced by both its molecular mass and degree of branching. A close look at the dextran structure reveals that it has hydroxyl groups and aldehyde groups (CHO) at terminal point, two conventional sites for chemical functionalization (Figure 2.3) [46].
BSA dextran conjugates have also been demonstrated to successfully encapsulate hydrophobic medications like ibuprofen. The decoration of dextran nanocarriers for medicinal applications has received particular attention due to its biocompatibility, biodegradability, nonantigenicity, and non-immunogenicity, dextran is a desirable material to use in the production of nanoparticles that will be used to deliver therapeutic targets. For example, doxorubicin has been delivered to the cancer cell’s nuclei using advanced drug delivery systems called dextran nanoparticles in chemotherapy [47–49].
Figure 2.3 Dextran.
Cellulose
Cellulose is the most typical and prevalent biopolymer known to exist on Earth. In 1838, Anselma Payen found cellulose in plant tissues and isolated it; he then identified its molecular formula as (C6H10O5) n. The first thermoplastic polymer made from cellulose was celluloid, created by Hyatt Manufacturing Company. Hermann Staudinger’s discovery of cellulose’s polymeric structure is merited [50]. The sources of cellulose include the plant kingdom (including jute, wheat straws, wood, hemp and cotton), as well as marine life (including tunicates), an algae (including valonia), bacteria (including acanthamoeba, acetobacter, and achromobacter), mineral and fungi sources. Cellulose is typically hydrophobic by nature and insoluble in the majority of organic solvents due to its large molecular weight and crystalline structure. On how much of it has been polymerized, most of the features of cellulose depend. With the use of processes like esterification and oxidation of cellulose, among others, many cellulose derivatives have been produced with better physicochemical qualities than the original form, such as higher water solubility and decent solubility in other organic solvents. Cellulose (Figure 2.4) and its derivatives are useful materials for their utilization in medicine administration, wound dressing, and various associated biomedical applications due to their low toxicity, desired biodegradability, significant biocompatibility, abundance in nature, and remarkable mechanical qualities [51, 52].
Figure 2.4 Cellulose.
Chondroitin Sulfate
The extracellular matrix (ECM) and cell surfaces contain a family of polysaccharides known as chondroitin sulphate (CS), which is often found coupled to proteins as proteoglycans. They are 4)-GlcA-(13)-GalNAc-alternating linear polysaccharides. 1-disaccharide units, whose hydroxyl (-OH) groups can be sulfated in different amounts and locations to create different CSs (GlcA = glucuronic acid, GalNAc = N-acetylgalactosamine) [53]. Chondroitin sulphates are hybrid structures made primarily of 4- or 6-O-GalNAc monosulfated disaccharides with only a small amount of non-sulfated disaccharides (CS-0). However, marine species have been shown to have disulfated (CS-B, CS-D, CS-E, CS-K, and CS-L) along with trisulfated (CS-M, CS-S, and CS-T) disaccharides [54]. An animal cartilage component called chondroitin sulphate is a glycosaminoglycan. Chondroitin sulphate can detect and connect with the CD44 receptor when it interacts with cancer cells, which significantly enhances the uptake of chondro sulfate-based DDS by cancer cells. Additionally, chondroitin sulphate can dissolve quickly in the presence of degrading enzymes (such hyaluronidase), this results in the drug release of DDS based on chondroitin sulphate [55]. Despite having high water solubility, the direct use of unprocessed chondroitin sulfate as a potent drug carrier will only lead to minimal drug usage. Studies have shown that cross-linking with chondroitin sulphate can generate a conjugate system that significantly increases the effectiveness of hydrophobic active compounds against tumors [56].
The cationic polymers and cationic liposomes needed to bind to pDNA in order to produce stable cationic polyplexes and lipoplexes. In B16-F10 cells, these cationic compounds showed excellent transgene effectiveness, but they also showed significant cytotoxicity and potent erythrocyte agglutination. The polyplexes and lipoplexes might be encapsulated by CS to produce stable anionic particles without changing their structural makeup. The ternary complexes surrounded by CS in B16-F10 cells showed good transgene efficacy with minimal cytotoxicity and agglutination. When given intravenously to mice, polyplexes exhibited a limited amount of transgenic effectiveness, but those that were encased in CS had far higher transgene effectiveness. The CS capsulation, however, reduced the high lipoplex transgenic effectiveness [57, 58]. Tetsuro Tomiyama et al
