Polymeric Nanoparticles as a Promising Tool for Anti-cancer Therapeutics

Polymeric Nanoparticles as a Promising Tool for Anti-cancer Therapeutics

Editors

Prashant Kesharwani

Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India

Kishore M. Paknikar

Nanobioscience Group, Agharkar Research Institute, Pune, India

Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, India

Materials Research Centre, Malaviya National Institute of Technology, Jaipur, India

Virendra Gajbhiye

Nanobioscience Group, Agharkar Research Institute, Pune, India

Table of Contents

Cover image

Title page

Copyright

Contributors

Preface

Chapter 1. Current Status and Future Challenges of Various Polymers as Cancer Therapeutics

1. Introduction

2. Major Challenges and Strategies to Overcome

3. Conclusion

Chapter 2. An Overview of Polymeric Nanoparticles as Potential Cancer Therapeutics

1. Introduction

2. Formulations of Polymeric Nanoparticles

3. First Generation Polymeric Nanocarriers

4. Second Generation Polymeric Nanocarriers

5. Third Generation of Polymeric Nanocarriers

6. Polymeric Nanoparticles in Clinical Setups

7. Future Perspective

8. Conclusion

Chapter 3. Polyacrylate Nanoparticles as a Promising Tool for Anticancer Therapeutics

1. Introduction

2. Polyacrylate Nanoparticles in Cancer Therapeutics

3. Safety Concerns of Polyacrylate-Based Nanoparticles

4. Future of Polyacrylates in Cancer Therapeutics

Chapter 4. Poly(alkyl cyanoacrylate) Nanoparticles as Promising Tools in Cancer Therapeutics

1. Introduction

2. Pharmacology of Poly(alkyl cyanoacrylate) Nanoparticles and Nanoparticle-Associated Drugs

3. Toxicity of Drug-Free and Cytostatic-Loaded Poly(alkyl cyanoacrylate) Nanoparticles

4. Efficacy and Safety of Poly(alkyl cyanoacrylate) Nanoparticle-Formulated Anticancer Therapeutics

5. Concluding Remarks

Chapter 5. Poly(α-hydroxy acid)-Based Nanoparticles for Drug/Gene Delivery for Cancer Therapy

1. Introduction

2. Polylactic Acid/Polylactic-Co-Glycolic Acid Nanoparticles: Properties

3. Nanoparticle Formulation Methods

4. Polylactic Acid/Polylactic-Co-Glycolic Acid Nanoparticles in Cancer Therapy

5. Conclusion and Future Prospects

Chapter 6. Polyester, Polyhydroxyalkanoate Nanoparticles as a Promising Tool for Anticancer Therapeutics

1. Introduction

2. Polyester Nanoparticles in Cancer

3. Polyhydroxyalkanoate Nanoparticles in Cancer

4. Conclusion

Chapter 7. Poly(Phospho Ester) and Poly(Phosphazene) Nanoparticles as a Promising Tool for Anticancer Therapeutics

1. Poly(Phosphoester) Nanoparticles

2. Poly(phosphazene) Nanoparticles

3. Conclusion

Chapter 8. Polycarbonate Nanoparticles as a Promising Tool for Anticancer Therapeutics

1. Introduction

2. Polycarbonate-Based Approach for Anticancer Drug Delivery

3. Synthetic Routes to Aliphatic Polycarbonates

4. Factors Influencing Design of Polycarbonate Nanoparticles

5. Summary and Conclusions

6. Future Scope

Chapter 9. Poly(Amino Acid) Nanoparticles as a Promising Tool for Anticancer Therapeutics

1. Introduction

2. Polymeric Micelles

3. Synthesis of Poly(l-amino acid)

4. Drug Delivery and Clinical Applications

5. Drug Delivery Systems Based on Anionic Poly Amino Acids

6. Drug Delivery Systems Based on Cationic Poly Amino Acids

7. Drug Delivery Systems Based on Neutral Poly Amino Acids

8. Conclusion

Chapter 10. Polyethylene Glycol Nanoparticles as Promising Tools for Anticancer Therapeutics

1. Introduction

2. Structure and Properties of Polyethylene Glycol

3. Properties of Polyethylene Glycol

4. Overview of Polyethylene Glycol Nanoparticles and PEGylation

5. Polyethylene Glycol Conjugates: Prominent Drug Carriers for Cancer Therapy

6. Clinical Status of Polyethylene Glycol

7. Future Perspective of Polyethylene Glycol

8. Conclusions

Chapter 11. Dendrimer-Based Nanoparticulate Delivery System for Cancer Therapy

1. Introduction

2. Paradigm of Nanobased Therapy in Cancer Management

3. Dendrimers in the Modern Therapeutic Era

4. Features Incorporated in Dendrimers for Drug Delivery

5. Common Types of Dendrimers Used for Cancer Therapy

6. Synthesis of Dendrimers

7. Limitations of Dendrimeric Delivery System

8. Applications of Dendrimeric Nanocarriers in Cancer Therapy

9. Drug Targeting in Cancer by Dendrimer-Based Delivery Systems

10. CoDelivery in Cancer Therapy by Dendrimers

11. Market Status of Dendrimers

12. Conclusion and Future Prospects

Chapter 12. Conjugated Polymer Nanoparticles as a Promising Tool for Anticancer Therapeutics

1. Introduction

2. History of Conjugated Polymers

3. Structure, Properties, and Methods of Synthesis

4. Use of Conjugated Polymers in Cancer Theranostics

5. Conclusion

Chapter 13. Microbe-Based Versatile Polymeric Bionanoplatforms in Anticancer Therapy

1. Anticancer Nanomedicines

2. Polymeric Nanomaterials

3. Need for Biomaterials

4. Seaweed-Polymeric Nanoplatforms

5. Bacterial-Polymeric Nanoplatforms

6. Fungal-Polymeric Nanoplatforms

7. Glucan-Based Nanoparticulate Systems

8. Microbe-Based Polymers: Biosynthesis and Surface Decoration of Metal Nanoparticles

9. Snags in Exploring Microbe-Based Nanoplatforms in Anticancer Applications

10. Conclusion

Chapter 14. Plant-Based Natural Polymeric Nanoparticles as Promising Carriers for Anticancer Therapeutics

1. Introduction

2. Plant-Based Natural Polymer Nanoparticles for Cancer Therapy

Chapter 15. Animal-Based Materials in the Formulation of Nanocarriers for Anticancer Therapeutics

1. Introduction

2. Albumin

3. Gelatin

4. Chitosan

5. Hyaluronic Acid

6. Chondroitin Sulfate

7. Summary and Conclusion

Chapter 16. Smart Polymersomes as Intelligent Nanomedicines in Cancer Treatment

1. Polymersomes

2. Conclusions and Future Directions

Chapter 17. Other Polymer Nanoparticles as Promising Tools for Anticancer Therapeutics

1. Introduction

2. Poly Sulfonic Acids

3. Poly Carboxylic Acids

4. Poly Boronic Acid

5. Poly Silamine

Chapter 18. Conclusion and Future Prospective of Polymeric Nanoparticles for Cancer Therapy

1. Introduction

2. Polyethylene Glycol

3. Polyalkyl Cyanoacrylate

4. Dendrimers

5. Gelatin

6. Albumin

7. Hyaluronic Acid

8. Chitosan

9. Polyesters

10. Poly Hydroxy Alkanoates

11. Cellulose

12. Alginate

13. Chondroitin Sulfate

14. Cationic Polymethacrylate

15. Hydroxy Acids

16. Polyurethane

17. Conclusion

Index

Copyright

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Contributors

H.M. Abdelaziz

Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Department of Pharmaceutics, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt

M.A. Abdelmoneem

Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Department of Pharmaceutics, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt

K. Abdelsalam

Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Sankalp Agarwal

Centre for Research in Engineering and Surface Technology, Dublin Institute of Technology, Dublin, Ireland

School of Food Science and Environmental Health, Dublin Institute of Technology, Dublin, Ireland

Nafees Ahemad,     School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia

Rajeshwar Reddy Aleti,     Discipline of Pharmaceutical Sciences, College of Health Sciences, UKZN, Westville Campus, Durban, South Africa

Mona Alibolandi,     Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

Ahmed Alsaqr,     Department of Pharmaceutics, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia

Narsireddy Amreddy

Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

Manjusha Annaji,     Department of Drug Discovery and Development, Auburn University, Auburn, AL, United States

Robert D. Arnold,     Department of Drug Discovery and Development, Auburn University, Auburn, AL, United States

R. Jayachandra Babu,     Department of Drug Discovery and Development, Auburn University, Auburn, AL, United States

Anish Babu

Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

Erem Bilensoy,     Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Ankara, Turkey

Hira Choudhury,     Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil, Malaysia

Rambabu Dandela,     Department of Industrial and Engineering Chemistry, Institute of Chemical Technology, Indianoil Odisha Campus, Samantpuri, Bhubaneswar, India

Vividha Dhapte,     Department of Pharmaceutics, Poona College of Pharmacy, Bharati Vidyapeeth University, Pune, India

Abishai Dominic

Department of Molecular and cellular medicine, Texas A&M Health Science center, College Station, Texas, United States

Department of Biomedical Engineering, Texas A&M University, College Station, Texas, United States

Sunil K. Dubey,     Department of Pharmacy, Birla Institute of Technology and Science (BITS), Pilani, Rajasthan, India

K.A. Elkhodairy

Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Ahmed O. Elzoghby

Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Harvard-MIT Division of Health Sciences & Technology (HST), Cambridge, Massachusetts, United States

Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

M.S. Freag

Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Harvard-MIT Division of Health Sciences & Technology (HST), Cambridge, Massachusetts, United States

Kavita R. Gajbhiye,     Poona College of Pharmacy, Bharati Vidyapeeth, Pune, India

Virendra Gajbhiye,     Nanobioscience Group, Agharkar Research Institute, Pune, India

Bapi Gorain,     School of Pharmacy, Faculty of Health & Medical Sciences, Taylor's University, Subang Jaya, Malaysia

Manish Gupta

School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia

Faculty of Pharmacy, DIT University, Dehradun, India

Mayank Handa,     National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow, India

Afzal Hussain,     Faculty of Pharmacy, S. Sinha College Aurangabad (a constituent unit of Magadh University, Bodh-Gaya, Gaya), Bihar, India

Rajshekhar Karpoormath,     Discipline of Pharmaceutical Sciences, College of Health Sciences, UKZN, Westville Campus, Durban, South Africa

Kanchan Kashyap,     Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER, Raebareli), Lucknow, India

Prashant Kesharwani,     Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India

Rajneet Kaur Khurana,     UIPS, Punjab University, Chandigarh, India

Kanchan Kohli,     Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, Delhi, India

Chandrakanth Kokare,     Department of Pharmaceutics, Sinhgad Technical Education Society's, Sinhgad Institute of Pharmacy (Affiliated to Savitribai Phule Pune University), Narhe, Pune, India

Pramod Kumar,     Nanobioscience Group, Agharkar Research Institute, Pune, India

Siva B. Lokesh,     National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow, India

Adityanarayan Mohapatra,     Department of Biomedical Science and BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Chonnam National University Medical School, Gwangju, Republic of Korea

Anupama Munshi

Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

Manimbulu Nlooto,     Discipline of Pharmaceutical Sciences, College of Health Sciences, UKZN, Westville Campus, Durban, South Africa

Kishore M. Paknikar

Nanobioscience Group, Agharkar Research Institute, Pune, India

Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, India

Materials Research Centre, Malaviya National Institute of Technology, Jaipur, India

Manisha Pandey,     Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil, Malaysia

Vishwas Pardhi,     Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER, Raebareli), Lucknow, India

In-Kyu Park,     Department of Biomedical Science and BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Chonnam National University Medical School, Gwangju, Republic of Korea

Kailash C. Petkar,     Government of India, Ministry of Science and Technology, Department of Scientific and Industrial Research, New Delhi, India

Varsha Pokharkar,     Department of Pharmaceutics, Poona College of Pharmacy, Bharati Vidyapeeth University, Pune, India

Kavita R. Gajbhiye,     Poona College of Pharmacy, Bharati Vidyapeeth, Pune, India

Rajagopal Ramesh

Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States

Mohammad Ramezani,     Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

Farah Rehan,     School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia

Munindra Ruwali,     Amity Institute of Biotechnology, Amity University, Gurgaon (Manesar), Haryana, India

Nida Sayed,     Nanobioscience Group, Agharkar Research Institute, Pune, India

Ash Sehdev,     10048 McLaughlin Road, Brampton, Ontario, Canada

Mahsa Shahriari,     Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

Rahul Shukla,     Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER, Raebareli), Lucknow, India

Sima Singh,     Discipline of Pharmaceutical Sciences, College of Health Sciences, UKZN, Westville Campus, Durban, South Africa

Ajit Singh,     Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER, Raebareli), Lucknow, India

Sumithra Y. Srinivasan,     Nanobioscience Group, Agharkar Research Institute, Pune, India

Prajakta Tambe,     Nanobioscience Group, Agharkar Research Institute, Pune, India

Saji Uthaman,     Department of Polymer Science and Engineering, Chungnam National University, Daejeon, Republic of Korea

Gamze Varan,     Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Ankara, Turkey

Cem Varan,     Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Ankara, Turkey

Samiksha Wasnik,     Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, California, United States

Georgi Yordanov,     Faculty of Chemistry and Pharmacy, Sofia University St Kliment Ohridski, Sofia, Bulgaria

Preface

Worldwide, every sixth death is due to cancer, making it the second leading cause of mortality. In 2016, an estimated 8.9   million people have succumbed to some type of cancer. This number is likely to double by 2035 if novel ways of combating the disease are not developed. A combination of chemotherapy, surgery, or radiation therapy is the standard treatment triad of cancer. As most cancers are detected at a late or metastatic stage, systemic chemotherapy is the primary option for the majority of patients. However, chemotherapy is beset with problems such as drug resistance, the effect on nontarget organs, and ensuing toxicity leading to severe side effects. These shortcomings of chemotherapy have prompted the development of newer strategies that seek to improve tumor targeting and decrease systemic toxicity.

Nanotechnology provides an opportunity to change the pharmacokinetic outline of drugs, reduce toxicity, and enhance the therapeutic efficacy by the development of multifunctional nanoparticles. Nanomaterials being investigated for cancer treatment include polymeric nanoparticles, solid lipid nanoparticles, liposomes, niosomes, dendrimers, micelles, and nanoemulsions. With their intrinsic properties like biodegradability, biocompatibility, ease of synthesis, and large-scale production as well as amenability to functionalization for effective targeting, polymeric nanoparticles are one of the most researched materials.

This book attempts to provide an insight into state-of-the-art polymeric nanoparticles in cancer therapeutics and its prospects. The book comprises 18 chapters that cover the entire range of polymeric nanoparticles, which have been explored as nanocarriers for drug delivery to treat cancers. Focusing on design, synthesis, and applications, the book will be a valuable resource for students, researchers, scientists, and anyone else interested in unraveling and utilizing the potential of polymeric nanoparticles in cancer therapeutics. We believe that the book, with its comprehensive coverage of fundamental and applied aspects of the subject, will prove immensely useful to its readers and stimulate further interest.

We thank all the authors for their valuable and timely contributions. This book brings pioneers of the field and early career scientists together, which is no doubt an indication of the commitment toward the advancement of cancer therapeutics, to be continued across generations to come to combat the most dreadful disease faced by humankind.

P. Kesharwani

K.M. Paknikar

V. Gajbhiye

Chapter 1

Current Status and Future Challenges of Various Polymers as Cancer Therapeutics

Pramod Kumar ¹ , Kavita R. Gajbhiye ² , Kishore M. Paknikar ¹ , ³ , ⁴ , and Virendra Gajbhiye ¹       ¹ Nanobioscience Group, Agharkar Research Institute, Pune, India      ² Poona College of Pharmacy, Bharati Vidyapeeth, Pune, India      ³ Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, India      ⁴ Materials Research Centre, Malaviya National Institute of Technology, Jaipur, India

Abstract

Cancer is the leading cause of death worldwide and its treatment has been a major concern for researchers and doctors. Severe side effects of prominent anticancer drugs have forced the research community to explore delivery vehicles to achieve drug delivery specifically to the cancer site. Among these, nanoparticles emerged as the most potential candidates. But of various metallic and inorganic nanocarriers explored for the purpose of drug delivery, none are without any toxic effect to normal cells. Such a scenario shifted focus of delivery vehicle research to biocompatible and nontoxic carriers leading to polymeric nanocarriers. Polymeric nanocarriers do not exhibit toxic effects as seen in case of metallic and inorganic ones. Most of the polymeric nanocarriers carry linkages that are labile to some or other responses like redox, enzyme, and pH. Further, these polymers can be modified easily to impart desired characteristics and thus hold tremendous potential as delivery vehicles for anticancer drugs. In this chapter, we have briefly given an overview of research in the field of anticancer drug delivery using various polymeric nanocarriers and hurdles that need to be overcome, along with future prospects.

Keywords

Biodegradable; Cancer; Multifunctional; Polymeric nanoparticles; Stimuli-responsive; Theranostics

1. Introduction

1.1 Poly(alkyl cyanoacrylates)

1.2 Poly(α-hydroxy acids)

1.3 Poly(orthoesters)

1.4 Poly(carbonates)

1.5 Poly(urethanes)

1.6 Poly(phosphazenes)

1.7 Poly(amino acids)

1.8 Dendrimers

1.9 Conjugated Polymers

1.10 Polyethylene Glycols

1.11 Animal-Based Polymers

1.12 Plant-Based Polymers

1.13 Microbe-Based Polymers

2. Major Challenges and Strategies to Overcome

3. Conclusion

References

1. Introduction

A major threat to public health looms in form of cancer. It is responsible for most human deaths globally. It results from the abnormality in homeostasis of the human body. Growth and division of human cells are tightly regulated processes governed by various checkpoints. The basic aim of these is to prevent any abnormal cell from proliferating. This is achieved by activating programmed cell death of abnormal cells. For example, proliferation of cells is stopped if any genetic defect is detected, and the cell undergoes the DNA repair process. If the damage is beyond repair, then cell death is its ultimate fate. Thus the human body maintains cells with normal homeostasis only and clears abnormal cells. But in a few cases such regulation malfunction is due to alteration or defect in regulatory molecules. In such a scenario, the cell proliferates in an uncontrolled manner and forms a tumor. With accumulation of more genetic changes, this benign tumor gains property to metastasize to other organs and form new tumors. Metastasis is the major cause of concern in cancer as it leads to spread of cancer throughout the body, making prognosis much more difficult. There are various therapies available for prognosis of cancer like chemotherapy, radiation therapy, hormonal therapy, and surgery (https://www.cancer.gov/about-cancer/treatment/types) [1].

Surgery has been known to be most effective but only if the diagnosis occurs at an early stage of cancer development. Thus doctors resort to other therapies before opting for surgery. Chemotherapy is the most widely used therapy. Drugs or a combination of drug targeting cellular processes important for the survival of cancer cells are targeted. But these molecules are incapable of differentiating between normal cells and cancer cells and thus target both cell types, resulting in high toxicity to normal cells of the human body. Such side effects have caused major concerns among doctors and researchers. As a result, various methods for treatment of cancer are being explored. Targeting anticancer drugs at a molecular level like inhibitors of tyrosine kinase, monoclonal antibodies, and various other compounds that home specifically to cancer cells have been developed in order to achieve better therapeutic efficacy while reducing toxicity to normal cells. Still, major hurdles including poor solubility in water and drug resistance restrict its application at clinical level. Researchers have further shown that usage of anticancer drugs in combination can solve this issue because of two reasons, a longer adaptation process that cancer cells will have to undergo if drugs target different processes, and the use of a combination may result in a synergistic effect resulting in pronounced efficacy [2]. With continuous research in the hunt of more potent anticancer drugs, a number of drugs that can be used for combination therapy have been increasing continuously. Numerous molecules have been identified that can target specifically crucial pathways of cancer cells [3]. Still, even after the discovery of numerous such promising anticancer drug candidates for combination therapy, their translation to in vivo is lacking due to optimal drug conditions being difficult to achieve. This results from different pharmacokinetic parameters of each drug.

The limitation of different pharmacokinetic behaviors of drugs for cancer therapy led to the development of drug delivery. Drug delivery can overcome the limitation of combination therapy by delivering these drugs specifically to the cancer site in a manner controlled both spatially and temporally. This could be achieved by using nanotechnology-based drug delivery carriers that can control the release of drugs specifically at the cancer site. The last decade has witnessed enormous exploration in nanotechnology-based nanocarriers or nanoparticles for delivery of drugs. These nanoparticles were synthesized using various types of polymers for encapsulation/conjugation of chemotherapeutic agents. These drug carriers were synthesized using natural, synthetic, or semisynthetic polymers to protect drug payloads from precipitation, renal clearance, protein adsorption, and nonspecific cell uptake in major organs such as the liver and spleen. Various types of biodegradable polymers have been explored for developing drug delivery carriers (Table 1.1) and each chapter of this book has been devoted to a specific category of polymeric nanoparticles that have been employed for delivery of anticancer therapeutics. In this chapter an overview of various polymers has been discussed briefly under different sections.

Table 1.1

1.1. Poly(alkyl cyanoacrylates)

The most typical property of poly(alkyl cynanoacrylate) (PACA) polymers is their polymerization in the presence of water. These are also biocompatible and biodegradable. The ester bond present in the side chain is easily hydrolyzed. The rate of hydrolysis is dependent on the length of alkyl chain, where the longer the length of side chain, more is degradation time. PACA degrades into water soluble poly(cyanoacrylic acid) and alkyl alcohol [4]. The FDA has also approved a few PACA derivatives (ethyl, n-butyl, and octyl cyanoacrylate). Apart from their biomedical application they have also been exploited as drug delivery systems. These polymers have opened new horizons for development of colloidal carriers of low toxicity with excellent biodegradability [5]. Targeted delivery devices prepared by conjugating ligands have demonstrated increased accumulation in tumors via receptor mediated uptake [4]. One such study reported chitosan-coated PACA nanoparticles decorated with folate for delivery of doxorubicin (DOX) specifically to cancer cells. Results demonstrated enhanced therapeutic effect of these nanoparticles on cancer cells expressing folate receptors [6]. Application of these polymers in bioimaging, specifically fluorescent imaging, has been explored by preparing PEGylated PACA nanoparticles incorporated with quantum dots [7].

1.2. Poly(α-hydroxy acids)

Poly(α-hydroxy acids) are synthetic polymers and have been exploited for anticancer drug delivery in a targeted and controlled manner due to properties like biodegradability and biocompatibility. These polymers are prepared from alpha amino acids. The first synthetic biodegradable polymer to be explored for drug delivery application was poly(glycolic acid) (PGA). PGA is crystalline in nature and provides great control over cargo release as it erodes rapidly when its ester backbone is cleaved nonspecifically. Another polymer of the same class, poly(lactic acid) (PLA), also has been explored widely for biomedical applications. This polymer is present in two different forms: D and L form. Copolymers of these two forms of PLA have been investigated for various properties desirable in clinical settings. Poly(D,L-lactic acid) (PDLLA) is amorphous in nature, whereas poly(L-lactic acid) (PLLA) is a semicrystalline polymer [8]. Furthermore, copolymers of glycolic acids and lactic acids, poly(lactide-coglycolide acid) (PLGA), have been studied extensively for development of targeted delivery systems [9].

PLGA has been approved by the FDA for usage in drug delivery owing to its outstanding biodegradability and biocompatibility. PLGA-based delivery systems have also been utilized for delivery of oligonucleotides and proteins along with anticancer drugs. A hydrolytic cleavage of eater linkages results in degradation of these polymers into biodegradable glycolic and lactic acids. The rate of degradation depends on chemical structure, crystallinity, molecular weight, glass transition temperature, and hydrophobicity [10]. Various hydrophilic as well as hydrophobic anticancer drugs such as 5-fluorouracil, paclitaxel (TAX), cisplatin, DOX, and docetaxel have been delivered specifically to cancer cells using these polymers [9]. Different FDA-approved products undergoing clinical evaluation like goserelin acetate injection, leuprolide acetate suspension, leuprolide acetate injection paclitaxel micelles, triptorelin pamoate injection, and others have proved that this polymer possesses the properties desirable for development of a biodegradable carrier. Further, these polymers have been explored for targeted delivery of the drug to cancer sites. To achieve this, these are modified with various ligands directed specifically to some molecules being expressed abundantly on the cancer cell surface. PLGA-based nanocarriers modified with ligands have been shown to deliver a high dosage of anticancer drug to tumor sites. Herein, aptamer-conjugated PLGA-b- polyethylene glycol (PEG) nanoparticles were loaded with cisplatin and evaluated in vivo in mouse xenograft models of prostate cancer. The results showed a comparable antitumor effect of a drug-loaded nanocarrier with that of free drugs; that is, conventional dosage form [11]. Further, these polymers have also been investigated for a combination therapy of cancer to overcome drug resistance and strengthen the anticancer efficacy. In one such study, codelivery of hydrophobic TAX and hydrophilic DOX was studied using methoxyPEG (mPEG)–PLGA-based nanoparticles in cancer cell lines (Fig. 1.1). This resulted in enhanced suppression of tumor growth in comparison to TAX or DOX alone [12]. A thermosensitive water soluble implant ReGel, made of PLGA–PEG–PLGA triblock copolymer, demonstrates release of TAX over 50   days [13].

One of the most explored polymers of this class is poly-ε-caprolactone (PCL), which is a poly lactone of semicrystalline nature. It consists of ester linkages that impart a biodegradable property to this polymer. The rate of degradation of PCL is slower than that of PLGA, which resulted in usage of this polymer to develop long-term delivery systems. Few other polymers of this class have also been studies as drug delivery systems like poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), and poly(valerolactone). PCL exhibits excellent solubility and also mixes well with different polymers, which makes it an attractive candidate for developing delivery systems using PCL and its various copolymers [14]. The major focus for developing PCL nanocarriers has been to enhance the efficacy of anticancer drugs while retaining their activity against cancer cells [15]. Other major uses of this nanocarrier have been in the development of biodegradable micelles, resulting in the controlled release of the cargo in response to a stimuli [16]. It has been used as a carrier to enhance the oral efficacy of cytotoxic drugs like DOX and TAX [17]. PEG-linked derivatives of PCL have been used for preparing nanoparticles that can be implanted after surgical reduction of the tumor [18]. Copolymer of another poly lactone, poly(p-dioxanone), with other types of polymers have been employed for tuning biodegradability of the carriers by introducing changes in hydrophobicity and the structure. For example, poly(p-dioxanone)-based micelles were prepared with amphiphilic block copolymer of chitosan-b-poly (p-dioxanone) and loaded with camptothecin. Cellular uptake and cytotoxicity studies on HeLa cells showed effective internalization and potent antitumor efficacy [19].

1.3. Poly(orthoesters)

Bulk eroding polymers like poly lactones have certain disadvantages that can be overcome using polymers with surface-eroding properties. Poly orthoesters (POEs) are such polymers, which degrade in the presence of acid due to bonds labile to hydrolysis on their surface. The degradation property of these polymers can be tailored by preparing copolymers of POE with other polymers. POEs are known to be biocompatible and exhibit a pH-dependent degradation property. The property of these polymers to respond to pH demonstrates its ability for development of pH-responsive delivery systems for cancer therapy [20]. The degradation rate and physical form of these polymers can be modulated by changing the starting materials (like diols or acids) used in the synthesis. These polymers are classified under four different categories (POE I, POE II, POE III, and POE IV). Among different types of POE, POE type IV has been shown to be the most biocompatible for development of stimuli responsive carriers [14]. The pH sensitive polymeric micelles prepared from block copolymers of PEG and POE have been reported to study the ability to deliver anticancer drugs specifically to tumors. The core of the micelles, which is formed from POE, degrades at endosomal pH (i.e., pH 5) and as a result the encapsulated drug is released within the cell. Results of a degradation study demonstrated the ability of POE-based micelles to be stable for 3 days at pH 7.4 while it lasted only 2   h   at pH 5.5 [20]. Another group reported POE-PEG micelles with pH-dependent release of TAX loaded within it [21].

Figure 1.1 Illustration of biodegradable amphiphilic copolymer nanoparticles loaded with both doxorubicin (DOX) and paclitaxel (TAX) using improved double emulsion method. Emulsification procedure used to generate double emulsions. Step (1), generating water-in-oil for encapsulations of DOX; step (2), generating water-in-oil-in-water for encapsulations of TAX. Green represents the oil phase containing amphiphilic copolymer and red represents the aqueous phase containing DOX. 

Reproduced with permission H. Wang, Y. Zhao, Y. Wu, YL. Hu, K. Nan, G. Nie, et al., Enhanced anti-tumor efficacy by codelivery of doxorubicin and paclitaxel with amphiphilic methoxy PEG-PLGA copolymer nanoparticles. Biomaterials 32 (2011) 8281–8290. doi:10.1016/j.biomaterials.2011.07.032. Copyright © 2011, Elsevier.

Poly(phosphoesters) (PPEs) are a class of POE material whose functionality and solubility profile can be modified with ease. It can be easily prepared from low costing monomeric units. Further, the ease of modification makes these polymers attractive for various pharmaceutical and biomedical applications [22]. These polymers possess the ability to degrade by hydrolysis or by enzymatic activity that cleaves the phosphoester bond. This results in breakdown products like diols, alcohols, and phosphates. Also, the phosphorous atom present in the polymer is pentavalent, which allows development of polymer prodrugs with relative ease [23]. Using this property of the polymer, a copolymer of PEG-b-PPE was conjugated to DOX through a hydrazone linkage. The anticancer activity was assessed on a xenograft mouse model and the results showed increased suppression of tumor in comparison to free DOX. For free DOX it was reduced to 800   mm³ while for a drug-polymer conjugate a reduction to 300   mm³ from a volume of 2000   mm³ was observed [23]. Targeting of tumors actively has also been explored using PPE polymers. Galactosamine-conjugated PCL-co-PPE nanoparticles were loaded with DOX and studied for anticancer activity against hepatocellular carcinoma. The anticancer activity of ligand modified nanoparticles was found to be higher than bare nanoparticles (i.e., without targeting ligand). This was attributed to the receptor mediated uptake of ligand modified nanoparticles [24].

1.4. Poly(carbonates)

Another class of polymers being explored for drug delivery applications with biodegradable property is poly(carbonates). These polymers have a backbone made up of carbonate groups that can degrade by hydrolysis and as a result they show low mechanical strength. These polymers are capable of undergoing either enzymatic or acidic degradation and the resulting products are not toxic [14]. The degradation of poly(carbonates) result in carbon dioxide and two alcohols. Further, their rate of degradation can be modulated by modifying the side chain groups of the polymer. The derivatives of polycarbonates have been studied for targeted delivery of anticancer drugs via polymeric micelles. For tumor targeting, these micelles were prepared using a triblock copolymer of urea-functionalized polycarbonate (the hydrophobic block), short poly(ethyleneglycol)-functionalized polycarbonate (hydrophilic block), and galactose-functionalized polycarbonate (hydrophilic block) and a diblock copolymer of polycarbonate without galactose [25]. Development of polymer-prodrugs conjugates using poly (carbonates) have also been explored. A conjugate of polycarbonate and DOX was prepared by conjugation of DOX to the polycarbonate through hydrazine linkages (pH sensitive). As a result, pH-sensitive behavior was observed; that is, a drug released at acidic pH and higher in vitro cytotoxicity was observed in cancer cell lines [26]. One research group investigated polycarbonate micelles for codelivery of DOX and thioridazine. Their results showed strong cytotoxic activity against cancer cells along with activity against cancer stem cells due to thioridazine. This combination provided a promising strategy for cancer treatment by targeting both cancer cells and cancer stem cells [27].

1.5. Poly(urethanes)

Poly(urethanes) (PUs) are a class of synthetic polymers with excellent biological performance owing to biocompatibility and biodegradability. These polymers also possess excellent mechanical properties and degraded enzymatically as well as hydrolytically due to the use of polyols during synthesis. As a result these polymers are excellent candidates for development of stimuli-responsive drug delivery systems [28]. The ease of modification of PUs allows functionalization of the carriers with ligands, targeting moieties and stimuli-responsive groups. For translation of PU-based delivery systems to in vivo, a holistic understanding of its behavior with well-defined and controlled structure is required with FDA approval [28]. A PU-based multifunctional micelle was developed with TAX loaded in it. The efficacy of these micelles was found to be higher than free TAX due to active targeting, stealth property, and easy uptake of developed micelles [29]. Biodegradable segmented PUs have been shown to address various issues, namely degradation rates, stimuli-responsiveness, and targeting ability. A redox-responsive delivery system was developed using PEG-polyurethane copolymer and DOX was loaded within it. The system demonstrated excellent anticancer activity with cytotoxicity lower than free DOX [30].

1.6. Poly(phosphazenes)

A group of polymers, inorganic in nature with phosphorous and nitrogen in its structure, known as poly(phosphazenes) have garnered tremendous interest. Substituting various groups in its backbone can facilitate tailoring of its rate of degradation along with hydrophilicity and hydrophobicity. Degradation of PPs results in ammonia and phosphate, which are nontoxic. Further, the phosphorous atom in the backbone being pentavalent allows development of prodrugs and systems for targeted delivery [14]. Owing to this property of PPs, a locally injectable, thermosensitive, and biodegradable hydrogel was prepared by conjugating DOX and poly(phosphazene). The hydrogel showed a sustained release of DOX and also effectively inhibited the growth of tumor in comparison to free DOX [31]. Further, these polymers have been studied for delivery of both hydrophobic [32] and hydrophilic [33] drugs. The polymer can be made pH-sensitive by substituting the side group, diisopropylamino (DPA), and with increase of DPA the membrane disrupting potential of the PPs can be improved. Further, PPs containing DPA demonstrated higher inhibition of P-glycoprotein (P-gp) and thus is being considered an attractive option for drug delivery in drug-resistant tumors overexpressing P-gp [34]. The potential of PPs to be used for targeted delivery of the drug have been demonstrated by conjugating folate-like ligands. Folate-decorated PPs with hydrazine linkages in their backbone and loaded with epirubicin hydrochloride were designed for targeted and pH-triggered drug release [35].

1.7. Poly(amino acids)

Poly(amino acids) consist of amino acids linked by nonamide bonds, and the hydrolytic degradation of this bond results in amino acids used in the synthesis. Poly(glutamic acid) (PG), poly(aspartic acid), polylysine, polyarginine, and poly L-histidine are some of the examples of this category of polymer class among which PG is one of the widely explored polymers [14]. These polymers offer multiple pendent functional groups for drug attachment resulting in polymeric prodrugs. One of the examples, PG-TAX, was developed as a macromolecular taxane for the first-line treatment of non-small cell lung cancer and is known to improve the therapeutic index of TAX [36].

1.8. Dendrimers

In recent years, dendrimer has emerged as a nonviral vector capable of delivery of drugs and nucleic acids to tumors and brain. These are polymeric in nature with multiple monomeric units branching radially from a core molecule resembling a tree (dendron in Greek) in structure [37]. The unique open-branched architecture of the dendrimer creates cavities that can be utilized for loading of cargos like drugs and nucleic acids. Further, ease of surface modification allows development of nanocarrier as per the need and thus, these have garnered much attention of researchers for drug and gene delivery applications [38]. The potential of these nanocarriers to be synthesized in a reproducible manner in specific-sized macromolecules has been described by the Vögtle group in the late 1970s [39], as well as the Tomalia group and the Newkome group in the 1980s [37,40–42]. Properties of dendrimers like low toxicity, high water solubility, controlled surface functionalities, and compact globular shape project them as ideal carriers for delivery of drugs to cancer cells [43]. Dendrimers can also facilitate the passive targeting of anticancer drugs to tumor tissues. This selective accumulation of macromolecules in tumors, termed the enhanced permeability and retention effect, is the consequence of the combination of reduced lymphatic drainage and increased permeability of the tumor vasculature to macromolecules [44]. The void spaces of dendrimers allow encapsulation of drugs, or alternatively, surface groups can be modified to permit covalent conjugation of drugs.

1.9. Conjugated Polymers

Conjugated polymers (CPs), or otherwise intrinsically conducting polymers (ICPs), are characterized by a backbone with poly-conjugated aromatic or alkyl-chain structures composed of alternating single and double bonds. While most of the polymers and organic molecules are insulators or semiconductors, the delocalized π-electrons of CP offer unique electronic conductivity and light absorbing properties [45]. Application of nanostructured CPs in biosensors is a widespread research interest. Apart from this, the delocalized π-electrons also give an interesting near infrared (NIR)-absorbing nature that is utilized for photothermal therapy and NIR imaging [46]. The unique optical and electronic properties, along with useful biological and material properties, craft nanostructured CPs as promising multifunctional candidates for multimodal therapy, imaging, and cancer theranostics [47,48]. Owing to the extraordinary properties, the use of CPs as a coating material over magnetic nanoparticles has gained surging interest and vast applications in the past decade (Fig. 1.2) [49]. These properties have not failed to be noticed by the researchers, and applications of CP in biomedicine have surged ever since the Nobel Prize in Chemistry in 2000. Since then, several CPs have been scrutinized among which Ppy, PANI, and PT are the most famous. Other CPs such as poly(phenylene-vinylene) and copolymers containing conjugated polymers are also reported in the literature, though less common. There is continuous research going on for usage of CPs as cancer theranostics. But this is still in the initial stages and lot more research needs to be carried out for its actual implementation.

1.10. Polyethylene Glycols

PEG is a biocompatible polymer with high solubility in water. It is used extensively in the preparation of polymeric drug delivery systems as a non-ionic polymer [50]. Passive targeting with PEGs in combination with active targeting delivery systems has been effectively employed to achieve a better therapeutic index of anticancer drugs. Further, the advent of stimuli-responsive linkages or moieties in PEGylated prodrugs shows better control over release of cargo within the tumor microenvironment. This opened a new era in the field of targeted drug delivery systems in cancer therapy. Modification of a molecule or nanoparticle by covalently attaching PEG to its surface is known as PEGylation. It prolongs the circulation time of the molecule or nanoparticle. PEGylation has been employed for small organic molecules, antibodies, nucleotides, peptides, liposomes, and also to various nanoparticle formulations [51–55]. The foremost hurdle in clinical translation of nanoparticle-based drug delivery systems is their short circulating lifetime. The bigger particles are taken up by reticuloendothelial systems whereas smaller particles are cleared rapidly by the kidney [56]. Here, modification with PEG can improve circulation half-life significantly. Owing to this property it has become the most widely used polymer in cancer drug delivery systems and as of yet there are more than 35 US FDA approved drug delivery systems with PEG on them [55]. One such example is DOXIL, which is a PEGylated liposomal formulation for DOX delivery [57]. PEGs as such have also been employed alone for drug delivery purposes.

Figure 1.2 Biomedical applications of conjugated polymer modified magnetic nanoparticles. 

Reproduced with permission S.Y. Srinivasan, K.M. Paknikar, V. Gajbhiye, D. Bodas. Magneto-conducting core/shell nanoparticles for biomedical applications. Chem. Nano. Mat. 4 (2) (2018) 151–164. Copyright © 2018, John Wiley and Sons.

1.11. Animal-Based Polymers

The most explored polymers of animal origin for anticancer drug delivery are chitin, chitosan, albumin, and gelatin. In nature, chitin and chitosan polysaccharides are obtained from the shells of crabs and prawns and are the most abundant polymers of their kind. For commercial purposes the shells of crabs, prawns, and shrimps are treated chemically to extract chitin [58]. Fermentation or enzymatic hydrolysis can also be employed for chitin production but these are expensive for industrial scale usage [59]. On other hand, chitosan is prepared by alkaline deacetylation of chitin. This polymer carries net positive charge on it. It is made up of D-glucosamine and N-acetyl glucosamine [60,61]. The degree of deacetylation governs characteristics like hydrophobicity, solubility, and its interaction ability with polyanions like nucleic acids. The deacetylation degree is a very important parameter since it controls the solubility, hydrophobicity, and chitosan ability to interact [62–64]. Chitosan is soluble only in acidic aqueous solutions due to the highly crystalline and rigid structure of the polymer as a result of hydrogen bonds between the acetoamido and primary amino groups. To overcome this barrier of solubility, functionalization of amino groups of chitosan is a promising approach. Such modification disrupts the crystalline architecture of chitosan, allowing solubility in more solvents [62]. Mucoadhesive property of this polymer along with its biodegradability and biocompatibility have garnered much interest in the scientific community for its usage in drug delivery system development [60,61]. In vitro and in vivo studies by numerous groups have proved anticancer properties of a chitosan-based delivery system and thus have accentuated its potential for cancer therapy [65].

Two proteins of animal origins, albumin and gelatin, have been widely studied for drug delivery applications in cancer therapy. Albumin is found in blood plasma of humans and it is the most abundant protein in plasma [66,67]. It is soluble in water with stability at range of pH (i.e., 4 to 9) and with the ability to withstand a temperature of 60°C for 10   h without any harmful effect. Being protein in nature, it is biodegradable, nonimmunogenic, and nontoxic [66–68]. Usage of albumin for development of a drug delivery system can have added benefits due to it being protein in nature. It could provide additional nutrition to the cells, and can be easily taken up by the cells by endocytosis and then broken down to amino acids in lysosomes. These amino acids can then be utilized for energy and as a nitrogen source. Owing to such beneficial properties, there is already albumin nanoparticle-based injectable formulation on the market for treatment of breast cancer known as Abraxane [68]. In the last few years, albumin-based nanoparticles have been tested for their ability to deliver a drug against various types of cancers. To assess this, Ji et al. [69] synthesized albumin nanoparticles with arginine-glycine-aspartic acid (RGD) peptide anchored to its surface. Conjugation of RGD was carried out with aim to target αvβ3 integrin on the surface of pancreatic cancer cells. This was used for delivery of gemcitabine to the cancer cells. Cellular uptake studies in BxPC-3 cells showed significantly higher uptake of RGD conjugated nanoparticles in comparison to bare nanoparticles. Furthermore, these nanoparticles loaded with gemcitabine showed enhanced antitumor effect both in vitro and in vivo. Gelatin is also a protein from an animal source that has been exploited for anticancer drug delivery [70]. Lee and group synthesized a gelatin-based platform for targeted delivery of siRNA to the tumor site [71]. Gelatin has low siRNA binding efficiency, therefore the group functionalized both siRNA and gelatin with the thiol group, which allowed covalent linking of siRNA to gelatin through disulfide linkages forming nanoparticles. The results demonstrated the ability of nanoparticles to protect siRNA from enzymatic degradation while effectively releasing siRNA in reducing conditions. Efficacy of the synthesized nanoparticles for siRNA delivery to cancer cells was assessed in melanoma cells expressing red fluorescence protein (RFP). Effective downregulation in RFP expression was observed in cells treated with siRNA containing nanoparticles. Further, in vivo studies showed higher tumor accumulation of nanoparticles than naked siRNA while inducing RFP silencing without detectable toxicity. This study further established gelatin nanoparticles as effective cargo delivery agent for cancer therapy.

1.12. Plant-Based Polymers

Cellulose, starch, and cyclodextrin are among the most widely exploited plant-based polymers for drug delivery. Biocompatibility of cellulose has encouraged research regarding different cellulose derivatives like hydroxy propyl cellulose, methyl cellulose, hydroxy propyl methyl cellulose, and carboxy methyl cellulose for biomedical applications. The advantages of cellulose lie in its biodegradability, chirality, nontoxicity, versatile morphology, and hydrophilicity, whereas rigid structure and insolubility are its disadvantages. A major focus of research regarding this polymer has been on the development of a delivery system for cancer drug delivery due to its ability to be recycled, low expenditure, and most of all its biodegradability [72]. These drug delivery vehicles have been found to be promising due to cargo delivery to the intended site with minimal premature release and gradual cargo release over time at the site [73]. Development of a cellulose-based targeted delivery system has also been attempted. One group of researchers developed folate-anchored cellulose magnetic nanoparticles for delivery of 5-fluorouracil. The results showed receptor mediated uptake of nanoparticles followed by higher cell death in a magnetic field [74]. Similarly, Yallapu et al. [75] prepared curcumin-loaded cellulose nanoparticles, PLGA nanoparticles, dendrimers, and magnetic nanoparticles. The group showed that curcumin-loaded cellulose nanoparticles showed the highest toxic effect on prostate cancer cells. Hence, the range of functional groups on the polymer along with its excellent biocompatibility opens promising perspectives that may lead to more research for targeted delivery of drugs to cancers using cellulose-based delivery systems.

Starch is yet another polymer obtained from plants. Structurally starch is composed of a linear chain as well as a branched chain of glucose (i.e., amylose and amylopectin). It is degraded easily by the action of the enzymes glucosidase and amylase. Thus starch is degraded to glucose, making them biodegradable in nature [72]. Due to excellent biocompatibility and biodegradability of starch, its derivatives have also been explored for drug delivery purposes. Owing to these properties, starch derivatives have been developed to be utilized instead of PEG, often used to modify nanoparticles to prevent nonspecific uptake by the cells. On similar lines, one group of researchers developed folate conjugated nanocapsules based on a hydroxyl ethyl starch derivative, which indicated the potential of polysaccharide-based platforms for targeted cargo delivery [76]. Starch-PEG copolymeric micelles consisting of redox responsive bonds were utilized to deliver DOX for cancer therapy. Results demonstrated glutathione responsive DOX release within the tumor, leading to significant tumor regression [77].

The next major polymer obtained from plant sources is cyclodextrin (CD). These are cyclic polysaccharides made up of glucose units with a (α-1, 4)-linked α-D-glucopyranose unit. The derivatives of CDs (i.e., α-, β-, and γ-CDs) are composed of six, seven, and eight glucose units, respectively. The three-dimensional structure is composed of an outer hydrophilic surface surrounding the hydrophobic cavity within. This amphiphilic nature of the polymer compelled researchers to explore the ability of CDs to deliver cargoes to a target site. Such application is supported by excellent biocompatibility, lack of immunogenicity, and low toxicity of CDs [78,79]. During loading of the drug, it is entrapped within the hydrophobic cavity of the polymer and thus, most of the studies regarding drug delivery applications have been directed toward formation of such complexes for treatment of cancer [80,81]. In a study, folate-anchored β-CD modified with pluronic F127-b-poly(ε-caprolactone) was utilized for loading DOX hydrochloride [82]. Results showed efficient uptake of the drug-loaded nanoparticles by the lung epithelial cancer cell line (A549), hepatoblastoma cell line (HepG2), KB and fibroblast normal cells. In yet another report, folate-anchored methyl-β-cyclodextrin (FA-M-b-CyD) was loaded with DOX and the antitumor effect was assessed against A549, colon-26, and KB cell lines [83]. The prepared formulation showed high antitumor effect. One group of researchers prepared transferrin-modified PEG-CD nanoparticles for siRNA delivery for the clinical phase trial I. They targeted the M2 subunit of ribonucleotide reductase (RRM2) (anticancer target) using siRNA against it to assess any reduction in its expression in solid tumors of volunteer patients. Biopsies of these tumors demonstrated localization of nanoparticles in the tumor. Furthermore, mRNA and the protein level of RRM2 was reduced significantly in comparison to untreated tissues [84].

1.13. Microbe-Based Polymers

A microbe-based polymer explored for drug delivery purposes is alginic acid. α-L-guluronic acid and β-D-mannuronic acid are the building units of alginate, which is a linear polysaccharide and anionic in nature. It also possesses excellent biocompatibility and biodegradation properties along with the ability to form gel. In order to assess its cargo delivery capability a group of researchers loaded DOX into alginate nanoparticles and assessed its ability to deliver DOX to the tumor site. Results showed uptake of nanoparticles into the cancer cells by endocytosis along with a higher tumor inhibiting effect in comparison to free drug in tumor xenograft in mice models [85]. The net negative charge on the surface of alginate nanoparticles prevented nonspecific uptake, thus suggesting its suitability to reduce side effects of the drug. In a similar fashion, alginic acid/acrylate copolymeric nanoparticles were formulated as a drug delivery vehicle for an anticancer drug like DOX [86]. Moreover, dual drug nanocolloids based on chitosan/alginic acid were prepared for the delivery of two drugs (lapatinib and TAX), and these nanocolloids showed enhanced tumor inhibition on multidrug-resistant ovarian cancer cell lines [87].

2. Major Challenges and Strategies to Overcome

The major challenge lies in the small size of nanoparticles, which makes them liable to be cleared easily from the blood circulation or to be sequestered by the reticuloendothelial system. This affects the payload delivering efficiency of the polymeric drug delivery system significantly [88]. Further, in spite of huge progress in targeted drug delivery to the tumor sites, passive targeting, extravasation through leaky vasculature, is still the primary process upon which tumor targeting relies. This impedes the complete realization of the potential polymeric nanoparticles hold. Interaction of nanoparticles with various proteins, tumor penetration, and cancer cell uptake also hampered successful clinical translation.

To explore the full potential of these systems active targeting is being investigated by the use of various ligands targeting cancer cells specifically. With respect to this, ligands like folic acid, monoclonal antibodies, aptamers, cell-specific peptides, and numerous small molecules have been studied for active targeting of tumors. But a ligand exclusive to the cancer cells only is still lacking, as most targets result from overexpression of