Nano Drug Delivery Strategies for the Treatment of Cancers

By Awesh K. Yadav and Umesh Gupta

Nano Drug Delivery Strategies for the Treatment of Cancers discusses several current and promising approaches for the diagnosis and treatment of cancer by using the most recent developments in nanomedical technologies. The book presents introductory information about the biology of different types of cancer in order to provide the reader with knowledge on their specificities. In addition, it discusses various novel drug delivery systems, detailing their functionalities, expected outcomes and future developments in the field, focusing on brain, mouth and throat, breast, lung, liver, pancreas, stomach, colon, bool, skin and prostate cancers.

The book is a valuable source for cancer researchers, oncologists, pharmacologists and nanotechnologists who are interested in novel drug delivery systems and devices for treatment of various types of cancer that take advantage of recent advances in this exciting field.

• Discusses a wide range of promising approaches for the diagnosis and treatment of cancer using the latest advancement in cutting-edge nanomedical technologies
• Provides foundational information on different types of cancer and their biology to help the reader choose the best nano drug delivery system for patients
• Presents novel drug delivery systems based on nanoparticles, microparticles, liposomes, self-assembling Micelles and block copolymer micelles

• Language: English
• Publisher: Academic Press
• Release date: Sep 3, 2020
• ISBN: 9780128197943

Book preview

Preface

Nano drug delivery system(s) refer to strategies and the development of such delivery vehicles that can be safely administered within body as needed for optimum therapeutic benefits while ensuring minimum to nil toxic effects.

Various methods have been used to construct nanocarriers to deliver the encapsulated drug to cancer cells directly. The development of such carriers modifies the anticancer drug accumulation and distribution thus producing the best possible therapeutic effects to the cancerous cells. Nano drug delivery by various drug delivery systems has emerged as a commanding technology for the treatment of various cancers. However, most of the techniques lack differentiation between cancerous and normal cells with associated loss of life. Anticancer drugs have a lot of limitations and reaches to cancerous cells in a limited concentration. To conquer such limitations researchers have prepared various target-specific nanoparticles to treat cancers.

The book contains 13 chapters including, Introduction: An Overview of the Anatomy and Physiology of Different Cancers, Novel Treatment Approaches and Conventional Therapies for Effective Treatment to Cancers, Nanoparticles and Brain Cancers, Nanoparticles and Mouth and Throat Cancer, Lactoferrin Based Nanocarriers for Cancer Therapy and Imaging, Nanoparticles and Lung Cancer, Nanoparti-cles and Liver Cancer, Nanoparticles and Pancreatic Cancer, Nanoparticles and Stomach Cancer, Nanoparticles and Colon Cancer, Nanoparticles and Blood Cancer, Nanoparticles and Skin Cancer, An Update in Drug Targeting Nanostrategies to Improve Cancer Treatment, Molecular Targets for Nanomedicine Based MDR Reversal Strategies in Cancer Therapy.

Each chapter discusses an introduction of cancer, development, current status of nano drug delivery system containing anticancer drug, and future prospects of the concerned nano drug delivery system with a particular cancer type.

We hope the book shall be a useful compilation for undergraduate, postgraduate, doctoral students, and researchers working in drug delivery research, research and development, and national research institutes. We hope to receive feedback, suggestions, and inputs from teachers, researchers and students that will help improve the next edition of the book.

Chapter 1

Emergence of novel targeting systems and conventional therapies for effective cancer treatment

Laxmikant Gautam¹, Anamika Jain¹, Priya Shrivastava¹, Sonal Vyas² and Suresh P. Vyas¹,    ¹Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, India,    ²Bundelkhand Medical College, Sagar, India

Abstract

As per the World Health Organization report (2018), cancer is one of the deadliest diseases in the world. Approximately, the second highest mortality is caused due to cancer. The uncontrolled growth and metastasis of abnormal cells are known as cancer. Currently, for the interdict of the rapid production of cancer cells, surgery, chemo-, or radiotherapy has a major contribution, but these conventional therapies are associated with various drawbacks such as normal tissue damage, poor aqueous solubility of bioactive(s), lack of selectivity, multidrug resistance, low bioavailability, toxicity, and side effects. For these limitations, numerous polymer or lipid-based novel drug delivery systems, that is, nanoparticles, liposomes, polymeric nanoparticles, solid lipid nanoparticles, etc., are discussed here, which are site-specific, and deliver the drug in a controlled and targeted manner. This chapter includes different novel drug delivery systems that have shown effective results over conventional therapies.

Keywords

Cancer; surgery; radiotherapy; chemotherapy; novel delivery system

1.1 Introduction

The World Health Organization clearly state in its report of 2018 that cancer is the second leading cause of death in the world, and it is assumed that it would increase exponentially to reach 12 million deaths per year by 2030 (Siegel, Miller, & Jemal, 2019). In developing and developed countries, a major cause of death is cancer due to bad habits (smoking tobacco, etc.) (Saadat et al., 2015). For the treatment of cancer, the therapeutic approaches used include chemotherapy, radiation, and surgery. Most of the time, combination therapy is applied to get the desired outcome and avoid resistance during cancer therapy. In cancer treatment, extensive heterogeneity in terms of response to drugs and drug resistance of melanomas are major impediments. The overexpression of antiapoptotic proteins and the emanation of anticancer drugs from cancer cells result in chemoresistance (Dry, Yang, & Saez-Rodriguez, 2016; Gandhi, Tekade, & Chougule, 2014; Xu et al., 2016). Although significant attempts have been made by researchers in the development of effective cancer therapies such as radiation, chemotherapy, surgery, immunotherapy, novel targeted approaches, or combinations of these approaches (Jain et al., 2018), the survival rate still remains quite low because the causes of cancer are still unknown. The survival rate and prognosis of cancer patients can be improved by early diagnosis at the early stages of cancer so that timely and effective treatment can be extended (Gautam & Anamikajain, 2019). Hence there is an urgent need for the development of improved alternative diagnostics and therapeutic strategies and interventions. The aim of these analyses of causes is to explore effective therapeutic opportunities to improve and increase the normal life span of cancer patients. Some of the conventional treatment procedures are described here for the treatment of cancer:

• Primary treatment: By using this treatment cancer cells are removed from the body or destroyed completely. In every type of cancer, overgrowth surgical removal is the most accepted method used in primary treatment. If patients are sensitive to the other types of treatments such as radiation therapy or chemotherapy then surgery remains a good option.

• Neoadjuvant or adjuvant treatment: The aim of this therapy is to kill those cancer cells that remain after the primary treatment, which can grow as a skipped lesson. Lai et al. worked on cancer in which miRNA was used as an adjuvant to increase the efficacy of small molecular inhibitor oncogenes (Lai, Eberhardt, Schmitz, & Vera, 2019). In clinical practice, in order to make primary treatment accessible, neoadjuvant therapy is given; for example, Lynn et al. report that in HER2-positive early breast cancer, an adjuvant treatment is given, which consisted of pertuzumab in combination with trastuzumab and chemotherapy (Howie et al., 2019).

• Palliative treatment: Palliative treatments may be given at any stage of cancer treatment, which may help to control or reduce the side effects of cancer treatments, including pain, shortness of breath, and toxicity (de Man et al., 2019).

The critical analysis of these methods suggests that treatment strategies are largely dependent on the stage and type of cancer. The analysis further suggests that some patients need single treatment, while in most cases, a combination of treatments is beneficial in the later stages of cancer as reported in patent no. US10301290B2 (Keilhack, Knutson, & Kuntz, 2019). Thus surgery, chemotherapy, radiation therapy, immunotherapy, hormone therapy, targeted drug therapy, etc., or a combination of any of these may be used for the treatment of cancer. In the present scenario, novel drug delivery approaches are being invented, targeted at different molecular targets such as the nucleus, mitochondria, cytoplasm, or endoplasmic reticulum for the effective treatment of cancer (Haider, Tiwari, Vyas, & Soni, 2019).

1.2 Conventional therapies for the treatment of cancer

1.2.1 Role of surgery for cancer treatment

Surgery is a medical branch that constitutes one of the treatment methods of cancer and that surgically removes cancer with the help of instruments. Surgery can involve cutting, abrading, suturing, or the management of acute illnesses and injuries as extricated from slowly progressing and chronic diseases.

1.2.1.1 Types of surgery

There are different types of surgery as shown in Fig. 1.1 and described here:

• Curative surgery: The removal of a tumor from the body is known as curative surgery; radiation may be used before and/or after this surgery. This type of treatment is often considered as a primary form of treatment. Parker et al. reported that through the use of curative surgery in rural Kenya, the survival rate of colorectal cancer patients increased (Parker et al., 2020). In another research work, Liu et al. showed the clinical significance of curative surgery in skin lymph node metastasis in pN1 gastric cancer patients, which resulted in increased survival times (Liu, Deng, et al., 2019).

• Preventive surgery: Preventive surgery is used to remove tissue that does not contain cancer cells, but may subsequently develop into a malignant tumor. For example, ipsilateral and contralateral breast cancer BRCA1 mutation, which is an age-specific risk is reduced by preventive surgery (Lubinski et al., 2019). Another preclinical study showed the preventive effect of surgical intervention in the recurrence of colon cancer (Majumdar, 2019).

• Diagnostic surgery: Diagnostic surgery is used to determine whether cells are cancerous; diagnostic surgery is extremely helpful. In this surgery, samples can be studied by different testing methods; for example, MRI (esophageal cancer) (Vollenbrock et al., 2019) or CT and MRI (gallbladder cancer) (de Savornin Lohman et al., 2019). The analysis will confirm which stage or type of cancer is present in a given sample.

• Staging surgery: In this surgery, the extent of the disease or cancer in the body is uncovered. For example, endometrial cancer (Watson et al., 2019), esophageal cancer (Patel et al., 2019), prostate cancer (Nandurkar et al., 2019), or gastric cancer by ¹⁸F-FDG PET-CT (Findlay et al., 2019), etc.

• Debulking surgery: This type of surgery is used to remove a portion of a cancerous tumor. It is used in certain situations when removing an entire tumor may cause damage to an organ or the body. As per the research, this method of surgery is mostly used in ovarian carcinoma (Ceppi et al., 2019; Heitz et al., 2019; Manning-Geist et al., 2019; Song & Gao, 2019), etc.

• Palliative with supportive surgery: Palliative surgery is used to treat cancer at advanced stages. It does not cure cancer, but is used to relieve discomfort or to correct other problems related to cancer. Also, another type of surgery helps with palliative surgery, which is a supportive surgery by nature. An example of supportive surgery is the insertion of a catheter to help with chemotherapy.

• Restorative surgery: Restorative surgery is sometimes used as a followup to curative or other surgeries to change or restore a person’s appearance or the function of an impaired body part. For example, women with breast cancer sometimes need breast reconstruction (plastic) surgery to restore the physical shape of the affected breast(s). Curative surgery for oral cancer can cause a change in the shape and appearance of a patient's mouth. Restorative surgery may be applied to address these visible deformations.

Figure 1.1 Various types of surgery.

There are several specialized surgeries that are used for cancer treatment. A list of some of these surgical treatments is provided here:

Cryosurgery: This surgery technique essentially involves the use of low temperatures to kill cancer cells. It is mainly used for skin cancer (Collins, Savas, & Doerfler, 2019), breast cancer (Pusceddu, Paliogiannis, Nigri, & Fancellu, 2019), pancreatic cancer (Zemskov et al., 2019), lung cancer (Kumar, Upadhyay, & Rai, 2019), and prostate cancer (Marra et al., 2019), etc.

Laser surgery: This technique uses beams of light energy instead of instruments to remove extremely small cancerous growths without destroying surrounding healthy tissue or to activate drugs to kill, shrink, or destroy tumors. Examples include thyroid cancer (Jiang, Solbiati, Zhan, & Mauri, 2020), glottic cancer (Rodrigo et al., 2019), prostate cancer (Greenwood et al., 2019), cervical cancer (Zhu, Wang, Pang, & Zhang, 2019), penile cancer (Shkolyar et al., 2019), gynecological cancer (Athanasiou et al., 2020), etc.

Electrosurgery: In this type of surgery, an electric current (radio frequency) is applied to increase focused and localized heat that kills cancer cells. This surgery is used to treat skin cancer (Collins et al., 2019), lung cancer (Zhang, Zheng, et al., 2019), ovarian cancer (Nieuwenhuyzen-de Boer et al., 2019), etc.

Microscopically controlled surgery: This surgery is useful when cancer affects parts of the body that are delicate and located deep in the body such as the eye. Skin layers are removed and analyzed. An example is basal cell carcinomas (Peters, Schubert, Geppert, & Moehrle, 2019; Peters, Schubert, Metzler, Geppert, & Moehrle, 2019), etc.

1.2.1.2 Risk and side effects of surgery in cancer treatment

Every procedure of cancer treatments suffers some risk. In the case of cancer treatment, it is important to learn about the types and stages of the cancer in question. Though science and medical technology have made surgery a safe and reliable treatment option, there is always a risk of potential problems and side effects. In many cases, however, the positive effects of surgery outweigh the risks. There may be some problems during surgery, including blood loss, damage to vital organs of the body, and adverse reactions. Some problems may occur after the surgery, including discomfort or pain, infections, and other illnesses such as blood loss or circulatory clot formation. The procedure of surgery in the treatment of cancer is risky. The application of surgery in the treatment of cancer provides a safe and reliable treatment option.

1.2.2 Role of radiotherapy for cancer treatment

Intense energy is generated by radioactive substances such as platinum, osmium, cobalt, or by functionalized equipment such as an atomic particle (linear) accelerator. Radiation conversely destroys cells that split rapidly and that encounter difficulty in repairing their DNA. Shi et al. studied that combining targeted therapies with radiation is beneficial for patients with lung cancer (Shi, Shao, Jiang, & Huang, 2016). Stereotactic body radiation therapy (SBRT) applied in pancreatic cancer showed late toxicity (Moningi et al., 2015).

1.2.2.1 Principles of radiation therapy

In this therapy, the cancer cells have been destroyed by using the source of energy. The radiation used is called ionizing radiation because it forms electrically charged particles or rays (γ, X-rays, UV rays, etc.,), and this energy can enter into and kill cancer cells or cause genetic changes, finally killing the bombarded cells (Fig. 1.2).

Figure 1.2 Role of radiation in targeting carriers for the treatment of cancer.

1.2.2.2 Some types of radiation therapy

For the treatment of cancer, different types of radiation therapies are used in different types of cancers, which include stereotactic ablative body radiotherapy for lung cancer (Phillips, Sandhu, Lüchtenborg, & Harden, 2019), volumetric modulated arc therapy for neck and head cancer (Leung, Wu, Liu, & Cheng, 2019), 3D conformal radiotherapy for rectal cancer (Luna & de Torres Olombrada, 2019), external beam radiation therapy (EBRT) for osteosarcoma (Tolomeo et al., 2019), image-guided radiotherapy (Shah, Agarwal, et al., 2020) for prostate cancer (Jereczek-Fossa et al., 2019), intensity-modulated radiation therapy for cervical cancer, etc. (Lin et al., 2019). EBRT is most commonly used (Tajaldeen, Ramachandran, Alghamdi, & Geso, 2019). In this process, a beam of electromagnetic radiation energy, that is, gamma rays or X-rays are generated by a linear accelerator and targeted (focused) at the cancer site. Christopher et al. indicated the use of EBRT by which prostate-specific antigen after neoadjuvant androgen suppression in prostate cancer patients, receiving short-term androgen suppression (Hallemeier et al., 2019). McDonnell et al. reported that long-term use of EBRT on patients suffering from tracheobronchial amyloidosis is well tolerated and many patients exhibited significant symptomatic improvement (McDonnell, Funk, Foote, Kalra, & Neben-Wittich, 2019).

1.2.3 Role of chemotherapy in cancer treatment

Cell autonomous genetic disease further converts into cancer as a consequence of alterations in tumor suppressor genes, genome stability genes, and oncogenes. Different treatments for cancer are used alone or in combination (Zitvogel, Apetoh, Ghiringhelli, & Kroemer, 2008). Chemotherapy is one of the three most conventional methods for oncological treatment, together with radiotherapy and surgery. Other treatments such as hormone therapy and immunotherapy can also be used in the case of certain types of cancer (Baskar, Lee, Yeo, & Yeoh, 2012).

The use of chemotherapy for cancer treatment started in the 20th century with attempts to narrow the multitude of chemicals that might affect the disease by developing methods to screen chemicals using transplantable tumors in rodents (DeVita & Chu, 2008). It was, however, for World War II-related programs, and the effects of the drugs that evolved from them provided the impetus to establish, in 1955, the national drug development effort known as the Cancer Chemotherapy National Service Center (Bud, 1978).

1.2.3.1 Principles of cancer treatment by chemotherapy

Chemotherapy uses chemicals to kill or inhibit malignant cells without much affecting the host cells (Alam et al., 2018). All cytotoxic chemotherapeutic agents exert their effects by disrupting the cell cycle by one or more mechanisms (Diakos, Charles, McMillan, & Clarke, 2014). Drugs that inhibit pathways involved in cell growth have been developed. Cancer cells differ from normal cells by their ability to grow and survive (Brown & Attardi, 2005). Acquired mutations to protooncogenes and tumor suppressor genes promote cell division because the normal cell cycle checkpoints are lost. The cells become insensitive to growth-inhibitory signals and evade programmed cell death (Harrington, 2011).

Drugs used in chemotherapy cause cell death by apoptosis, either by directly interfering with DNA or by targeting the key proteins required for cell division. Unfortunately, they can also be cytotoxic to normal dividing cells, particularly those with a high turnover such as the bone marrow and mucous membranes (Dickens & Ahmed, 2018). Chemotherapeutics are classified in one of two ways, that is, by their cell cycle effects or by their biochemical properties. Classifying them by their cell cycle specificity is useful because it influences how drugs are scheduled and combined for maximal effect (Fernando & Jones, 2015).

1.2.3.2 Indications for chemotherapy

• Palliative: Palliative chemotherapy can often significantly improve symptoms and overall quality of life. Palliative chemotherapy improves survival in some cancer types. Clinical trials of palliative chemotherapy are focused on overall survival and improving response rates without significantly increasing toxicity (Glimelius et al., 1995; Karavasilis et al., 2008).

• Curative: A number of cancers are extremely sensitive to cytotoxic chemotherapy. Testicular tumors, lymphomas, acute leukemias, and many pediatric malignancies respond so well that chemotherapy may be curative even in extensive disease. If chemotherapy is given with a curative intent, short-term toxicity is considered more acceptable and, therefore, many of these treatments are extremely toxic (e.g., high-dose chemotherapy) (Frei, 1985).

• Adjuvant: Many patients may be cured of their disease after surgery or primary radiotherapy, but many others relapse and die due to micrometastatic disease that is undetected at the diagnosis level. Chemotherapy may be an adjunct to primary therapy to kill micrometastases. Adjuvant chemotherapy is used routinely in the treatment of breast cancer (Rampurwala, Rocque, & Burkard, 2014; Saurel, Patel, & Perez, 2010).

• Neoadjuvant: The aim of neoadjuvant therapy is to treat micrometastases not visible with conventional imaging. It may also reduce the size of tumors, permitting surgery or allowing for a less radical procedure to be done. Examples include neoadjuvant therapy in breast cancer, enabling women to undergo a wide local excision rather than a mastectomy; it is also used routinely in the management of esophageal cancers and osteosarcomas (Abdel-Bary, El-Kased, & Aiad, 2009).

Resistance to chemotherapy is one of the main reasons for treatment failure, and in any given tumor type, there are usually a combination of different mechanisms that contribute to drug resistance; examples include reduced delivery of cytotoxic agents to the cell, decreased drug uptake, decreased drug activation, increased drug efflux, alteration in target protein, increased DNA repair, increased drug metabolism, and detoxification (Johnstone, Ruefli, & Lowe, 2002; Luqmani, 2005). Although there are strategies under development to reverse drug resistance, currently, the only realistic choice for clinicians is to switch to an alternative cytotoxic drug or a combination. The absence of a valid alternative normally results in the cessation of chemotherapy and switching to symptomatic control (Caley & Jones, 2012).

1.3 Novel approaches for the treatment of cancer

1.3.1 Lipid-based nanomedicines

1.3.1.1 Liposomes

Liposomes are bilayer structures made up of phospholipids that have the capacity to deliver both hydrophilic and hydrophobic drugs as payloads. Liposomes are lipid-based nanocarriers that were introduced by Bangham et al. in 1965. It has also been reported that univalent cations and anions spontaneously diffuse out from the liquid crystal of lecithin, similarly to how small ions cross the cell membrane in a biological system (Alavi, Karimi, & Safaei, 2017). Liposomes emerge as potential drug carriers for the delivery of therapeutics to their target sites, which is particularly important in cancer therapy due to their ability to decrease the side effects of anticancer drugs and improve the efficacy. A major drawback associated with anticancer drugs is their toxicity to both normal and cancer cells; however, this can be minimized by designing active and passive targeting. Anticancer efficacy can be enhanced by increasing the accumulation of liposomes at the target site (Yingchoncharoen, Kalinowski, & Richardson, 2016).

Advantages of the use of liposomes as drug carriers are (Jain et al., 2018):

• Liposomes are biocompatible in nature.

• Due to the amphiphilic properties of phospholipids, liposomes can encapsulate hydrophilic drugs in their core and lipophilic drugs in their lipid layer and are considered to be versatile drug carriers.

• Surface modification with PEG enhances the circulation time in the bloodstream.

• Targeting ligands associated with liposomes may specifically target tumor sites.

Ikemoto et al. reported the use of Bauhinia purprea agglutinin (BPA)-PEG-modified liposomes encapsulating doxorubicin for the treatment of prostate cancer. BPA is a lectin, which recognizes galactosyl glycoproteins and glycolipids on cancer specimens. After i.v. injection into DU145 solid cancer–bearing mice, it was observed that BPA-PEG-LP accumulated preferentially at cancer tissue and efficiently attached to prostate cancer tissue. BPA-PEG-LP-DOX considerably decreased DU145 cancer cell growth, while at the same dose, PEG-LP-DOX was less effective. Thus it could be an effective drug carrier for the treatment of prostate cancer (Ikemoto et al., 2016).

Petrilli et al. used cetuximab, an antiepidermal growth factor receptor (EGFR) antibody with 5-fluorouracil (5-FU) for the treatment of squamous cell carcinoma (SCC). The coadministration of an antibody (cetuximab) with an anticancer drug (5-FU) allows for the selective delivery of therapeutics to cancer cells. In vitro cell uptake studies revealed that the cellular uptake of cetuximab–immunoliposomes by EGFR-positive cells was 3–5 times greater than that of plain liposomes. In vivo studies suggested that this formulation decreased the tumor volume by more than 60% as compared to the negative control and by 50% when the 5-FU solution and plain liposome treatments were used. Additionally, iontophoresis increased the reduction of the tumor volume by twice as compared to the subcutaneous delivery of the 5-FU solution and plain liposomes. Histopathological studies reveal that subcutaneous administration iontophoresis of formulation is efficacious than for decreasing cell proliferation. Thus topical delivery of cetuximab–immunoliposomes incorporating 5-FU via iontophoresis is an effective strategy for the treatment of SCC (Petrilli et al., 2018).

Liposomal nanodrugs exhibit excellent results in preclinical and clinical experiments in cancer patients; various liposomal nanodrugs have been exploited as nanomedicine for cancer. Feng et al. conjugated the anticancer drug cisplatin with phospholipid along with other lipids. By doping with lipophilic dye (1,1′-dioctadecyl-3,3,3′,3′-tetramethyl indotricarbo cyanine iodide; DiR) with near IR absorbance and fluorescence, the resulting DiR–cisplatin liposomes have been established as effective probes for bimodal imaging. DiR–cisplatin liposomes exhibit an increased therapeutic efficacy when combined with photothermal chemotherapy. Liposomal carriers, thus, have emerged as efficient carriers for proteins as well as small hydrophilic molecules. The prodrug-based approach with tunable drug compositions, passive uptake, and simultaneous loading of different types of diagnostic and imaging agents makes this strategy attractive (Feng et al., 2016). Some liposomal formulations for cancer treatment are listed in Table 1.1.

Table 1.1

1.3.1.2 Niosomes

Niosomes have a bilayer structure similar to that of liposomes that additionally contains nonionic surfactants in an aqueous phase. They are biodegradable, nonimmunogenic, biocompatible, show greater stability, have a long shelf life, and can deliver a therapeutic to its target site in a sustained manner. Different types of nonionic surfactants are utilized for the formation of niosomes such as alkyl ether, alkyl esters, alkyl amide, fatty alcohols, etc. (Ag Seleci, Seleci, Walter, Stahl, & Scheper, 2016).

Niosomal drug delivery systems offer various advantages over conventional systems such as allowing for a reduction of dose due to their targeting mechanism, thereby decreasing the exposure of therapeutics to normal cells. Water-based vehicles are used in the preparation of niosomes, which exhibit better patient compliance as compared to oil-based systems. The oral bioavailability of a given drug is also enhanced by delaying systemic clearance and providing protection to the drug upon oral absorption from the biological environment. Niosomes are osmotically active and enhance the stability of drugs. Controlled release can be obtained using niosomes due to their vesicles, which act as a depot preparation, and thus, release the drug in a sustained manner; also niosomes are biocompatible, nonimmunogenic, biodegradable, and do not require any special storage conditions (Khan & Irchhaiya, 2016).

Kulkarni et al. developed tamoxifen- and doxorubicin-loaded self-assembled niosomes for breast cancer treatment. The entrapment efficiencies of tamoxifen and doxorubicin were found to be 74.3% and 72.7% respectively. Drug release studies revealed that the drugs were released in a sustained manner for up to 3 years. Cytotoxicity studies on an MCF-7 cell line revealed a 15 times improvement (0.01 mg/mL) and a greater synergistic effect of the formulation as compared to the plain drug combination (0.15 mg/mL). Thus niosomes appear to have potential in the treatment of breast cancer (Kulkarni & Rawtani, 2019).

Pawar et al. prepared an N-lauryl glucosamine–anchored doxorubicin niosomal formulation in which a glucose transporter was used as a targeting ligand. The N-lauryl glucosamine was synthesized and incorporated into doxorubicin-loaded niosomes using cholesterol as a membrane stabilizer, Span 60 as a surfactant, and diacetyl phosphate as a stabilizer. The formulation exhibits a 110 ± 5 nm particle size, a −30± 5 mV zeta-potential, and a 95% entrapment efficiency. The niosomal formulation was more cytotoxic with an IC50 value of 0.830 ppm as compared to the nontargeted formulation with an IC50 value of 1.369 ppm in B6F10 melanoma cell lines. In vitro studies suggested that the targeted niosomal formulation was selectivity internalized and showed a greater retention time as compared to the nontargeted niosomal formulation and free doxorubicin. Hence the NLG-anchored niosomal formulation of doxorubicin was more cytotoxic with a receptor binding potential and internalization, thus, seeming to be a promising strategy for cancer therapy (Pawar & Vavia, 2016). Other examples of niosomal formulations used for cancer treatment are listed in Table 1.2.

Table 1.2

1.3.1.3 Ethosome

There are various drawbacks associated with oral drug delivery such as the degradation of therapeutics by gastrointestinal tract enzymes, first-pass metabolism, and irritation in gastric mucosa, while the pain associated with parental drug delivery systems limit their uses. Hence transdermal drug delivery systems are preferred by patients. Ethosomes are interesting, preferred, innovative drug delivery systems. Drugs with poor penetration ability through the skin can be delivered using ethosomes. Basically ethosomes are ethanolic liposomes that are composed of lipid vesicles having phospholipids; the alcohol used may be ethanol or isopropyl alcohol in high concentrations. The unique structure of ethosome is due to the high concentration of ethanol with an alcohol concentration of 20%–30%. Phosphatidyl choline, phosphatic acid, alcohol, water, phosphatidyl inositol, and hydrogenated phosphatidyl choline are some phospholipids that are used in the preparation of ethosome (Jaiswal, Kesharwani, Kesharwani, & Patel, 2016).

1.3.1.3.1 Ethosomal drug delivery systems showed various benefits

As compared to transdermal and dermal drug delivery systems, ethosomal drug delivery systems possess various advantages such as (Chauhan, Pandey, Joshi, Dubey, & Jain, 2018):

• Large molecules such as peptides and proteins can be delivered via this route.

• Penetration and permeation of drugs are enhanced when delivered through the skin.

• Patient compliance is enhanced due to it being administered either in a gel or cream form.

• Different physicochemical characteristics are shown by drugs entrapped within ethosomes.

• Ethosomes are composed of nontoxic raw materials.

Jain et al. prepared ethosomes loaded with a carbopol hydrogel formulation for transdermal delivery. They screened various carbopols (C71, C934, C974, C941, and C971), out of which, C934, C974, and C971 grades were selected and used further for their flow and viscoelastic properties. The ethosomal formulation loaded with the C974 hydrogel in concentrations of 0.50% and 0.75% w/w respectively exhibited considerable plastic flow with different yield stress and relatively frequency independent elastic (G′) and viscous (G″). In vitro, skin permeation studies revealed that the ethosome loaded with the C974 hydrogel with a 0.5% w/w concentration of polymer showed a comparable permeability through the skin. Thus C974 allows for a high permeation of diclofenac and acts as a potential vehicle system for ethosomal vesicles (Jain, Patel, Madan, & Lin, 2016).

In another study by Jin et al., eugenol-entrapped ethosome nanoparticles (ELG-NPs) were prepared. ELG-NPs were optimized with 0.5% eugenol, 2% lecithin, and 30% ethanol. The nanoparticles were 44.21 nm in size with an 82% entrapment efficiency. This formulation showed antibacterial activity (>93%) against fruit pathogens, which was higher than the free eugenol. Permeability studies revealed that eugenol delivered transdermally with ethosome nanoparticles was 6 times greater than free eugenol. Slow-release and prolonged antibacterial action were achieved through the use of ELG-NPs. Thus this seems to be a potential strategy with wide applications such as in cosmetic, agricultural, food, and medical areas (Jin, Yao, Qin, Chen, & Du, 2019). Some ethosomal formulations and their results are shown in Table 1.3.

Table 1.3

1.3.2.4 Transferosome

Transferosomes are used for transdermal drug delivery systems; they are a special variation of liposomes that contain phosphatidyl choline and an edge activator. They penetrate the stratum corneum transcellularly or via an intracellular route through the generation of an osmotic gradient. Transferosomes possess various benefits such as being biocompatible, having a wide range of solubilities, greater penetration, and being biodegradable, etc. The transferosomes are applied in the transportation of large molecular weights compounds, transdermal immunization, controlled release and targeted delivery to the peripheral subcutaneous tissue, etc.(Solanki, Kushwah, Motiwale, & Chouhan, 2016).

1.3.2.4.1 Characteristics of transferosomes

The ideal transferosomes should possess certain characteristics, including (Chaurasia, Singh, Arora, & Saxena, 2019):

• The ability to be modified by tapered squeeze without caliper loss.

• They have their own bases, which are expressed by the deliquescent and aquaphobic tribes.

• The superior twisted afford to allow to administer the whole cyst.

• The vermicular cyst has the assured greater magnitude adaptable as compared to liposomes.

Hadidi et al. prepared bovine lactoferrin–loaded transferosomal vesicles for the transdermal delivery of the treatment for genital warts. Lactoferrin is a member of the transferrin family, which shows antiviral activity against human papillomavirus. The transferosomes were prepared by two methods, that is, reverse-phase evaporation and thin-film hydration methods using cholesterol, lecithin, DOTAP, SDS, Tween 80. These exhibited a 100 nm size with a 91% entrapment efficiency. In vitro studies revealed that the IC50 value of transferosomal lactoferrin was low as compared to the free lactoferrin (Hadidi, Saffari, & Faizi, 2018).

Kumar et al. prepared acyclovir-loaded transferosome to increase the penetration through the skin. The acyclovir transferosomes were optimized and a carbopol 934 gel base was used to carry the transferosomes. The gel was evaluation for viscosity, pH, in vitro penetration, and spreadability. The prepared formulation showed a greater entrapment efficiency ranging from 65% to 81% with smaller particle sizes, that is, from 181.9 to 401.8 nm. An in vitro release study revealed that there is an inverse relationship between entrapment efficiency and in vitro release. The release profile follows the Korsmeyer–Peppas model. Thus acyclovir incorporated in transferosomes can penetrate deeper into the skin (Kumar, Nayak, & Ghatuary, 2019). Some transferosomal formulations and their results are shown in Table 1.4.

Table 1.4

1.3.2.5 Nanoemulsion

A nanoemulsion is a biphasic dispersion of two immiscible liquids, either oil in water (o/w) or water in oil (w/o), that is stabilized by a surfactant. It forms an ultrafine dispersion having unique characteristics such as differential drug loading, visual properties, and viscoelastic properties. The mean droplet diameter of nanoemulsions is generally less than 500 nm. A clear or hazy appearance is obtained with a small droplet size, while a milky white appearance occurs with a coarse emulsion. A nanoemulsion can be sometimes interchanged with a mini or submicron emulsion, but it should not be mixed with a microemulsion. Nanoemulsions are classified based on their constituents and the relative distribution of the internal dispersed phase. They can be termed as biphasic (o/w or w/o) or multiple nanoemulsions (w/o/w) (Singh et al., 2017).

Shanmugapriya et al. formulated a nanoemulsion of astaxanthin and α-tocopherol with Sodium caseinate using spontaneous emulsification and ultrasonication for the production analysis of intracellular reactive oxygen species (ROS) in apoptosis. Both astaxanthin and α-tocopherol have the potential to induce ROS synthesis in the cytosol, ER, and mitochondria. Nanoemulsions exhibit high stabilities with small sizes and zeta-potential of spherical droplets with faster cell penetration and lesser toxicity. This type of formulation exhibits considerably high therapeutic effects against cancer. Thus it may be a potential way to eradicate cancerous cells and seems to a promising strategy (Shanmugapriya, Kim, & Kang,