Recent Advances in Nanocarriers for Pancreatic Cancer Therapy

Recent Advances in Nanocarriers for Pancreatic Cancer Therapy reviews thriving strategies concerning pancreatic cancer therapy, thoroughly describing the most recent developments in emerging modern drug delivery systems focused on, and derived from, nanotechnology. By providing a holistic understanding of the molecular pathways, conventional therapy and novel nanocarriers mediated drug delivery against pancreatic cancer, this work can be considered a complete package. The book offers a solution to the dissemination of data from a broad range of resources by providing an overview of the molecular pathways and conventional therapy of pancreatic cancer, the application of various nanocarriers, and more.

This book equips scientists, clinicians and students to make rational treatment approaches based on nanomedicine for improving and extending the human life against pancreatic cancer.

• Explains the complete journey of nanomedicine-based approaches in pancreatic cancer drug delivery from fundamental to most recent applications
• Provides information about various approaches for the diagnosis and treatment of pancreatic cancer using the latest advancement in cutting-edge nanomedical technologies
• Discusses the perspectives of the technologies explored to date based upon the fi ndings outlined in highly organized tables, illustrative fi gures, and fl ow charts for easy consult and comprehension

• Language: English
• Publisher: Academic Press
• Release date: Oct 22, 2023
• ISBN: 9780443152887

Book preview

Part A

Overview, molecular pathways and conventional therapy of pancreatic cancer

Outline

Chapter 1 An overview of the anatomy, physiology, and pathology of pancreatic cancer

Chapter 2 Different combination therapies pertaining to pancreatic cancer

Chapter 1

An overview of the anatomy, physiology, and pathology of pancreatic cancer

Farzad Rahmani¹, ² and Amir Avan¹, ², ³, ⁴, ⁵,    ¹Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran,    ²Basic Medical Sciences Institute, Mashhad University of Medical Sciences, Mashhad, Iran,    ³College of Medicine, University of Warith Al-Anbiyaa, Karbala, Iraq,    ⁴School of Mechanical, Medical and Process Engineering, Science and Engineering Faculty, Queensland University of Technology, Brisbane, QLD, Australia,    ⁵Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia

Abstract

Pancreatic cancer is one of the most aggressive malignancies around the world with more than 466,000 deaths in 2021. Despite recent improvements in screening, diagnostic, and therapeutic methods, patients with pancreatic cancer exhibit dismal prognoses and lower survival rates. Tumor progression with aggressive features and drug resistance are the main reasons for the failure of current therapeutic methods against pancreatic cancer. Therefore, a better understanding of the anatomical and physiological characteristics of the pancreas may provide more information related to better management of pancreatic cancer. Here we present a brief overview of the anatomy, physiology, and pathology of pancreatic neoplasia with a special focus on both the exocrine and endocrine pancreas. First, we explain the anatomy of the pancreas and describe the basic anatomical characteristics of this organ. Next, we focus on the physiologic functions of the endocrine and exocrine parts of pancreas and their role in the secretion of various hormones and digestive enzymes. In the last part, the pathology of several pancreatic endocrine or exocrine neoplasms is presented and their pathological characteristics are described.

Keywords

Pancreatic cancer; endocrine; exocrine

1.1 Pancreas anatomy

Pancreas is a glandular organ, which is morphologically divided into head, neck, body, and tail (Fig. 1.1). The average size of this gland is 14–18 cm long, 2–9 cm wide, 2–3 cm thick, and 80–100 g in weight [1–3]. The pancreas is a long, conical organ located behind the abdomen or behind the stomach. The widest portion on the right side of the pancreas is called the head, which is related to the duodenum. The neck of the pancreas connects the head to the body. The left side of the organ is called the body of the pancreas, which ends in the tail [4]. The tail is the narrow end of the pancreas that secretes insulin and digestive enzymes [5]. The main pancreatic duct begins in the tail portion, which transfers pancreatic secretions to the head section and often joins the bile duct in this section and forms the hepatic ampulla of the pancreas, which opens to the duodenum. The pancreas is made up of two different types of functional units including endocrine and exocrine tissues, which are introduced in the next section [6,7].

Figure 1.1 Schematic representation of pancreatic Langerhans islets cells.

1.2 Pancreas physiology

The pancreas as an important part of the digestive system has a major role in the digestion and absorption of nutrients and regulation of body metabolism by production and release of various digestive enzymes and pancreatic hormones [8]. The pancreas consists of two separate glandular systems including exocrine and endocrine pancreas. The acinar cells that constitute most of the exocrine mass of the pancreas are involved in production and secretion of the pancreatic juice containing multiple enzymes, including peptidase, lipase, and amylase enzymes as well as alkaline fluid, which are released into the duodenum [9,10]. In contrast, the endocrine cells that make up a small part (1%–2%) of the pancreas are implicated in secretion of several pancreatic hormones, which are released into the bloodstream [11]. For better understanding, the functions of pancreatic exocrine and endocrine parts are discussed separately.

1.2.1 Endocrine pancreas

The pancreatic endocrine portion consists of multiple distinct clusters of cells known as the Langerhans islet cells, which are scattered throughout the pancreas, especially in the tail area. The number of islets in the pancreas is between 1 and 2 million, but they contribute to less than 2% of the total mass of the pancreas [12]. As shown in Fig. 1.1, Langerhans islets contain various types of hormone-producing cells including alpha, beta, delta, and F cells, which can be identified by their morphological and staining characteristics. Beta cells in the center of the islets are surrounded by alpha, delta, and F cells. All cells communicate with each other through extracellular spaces and gap junctions. This type of cell arrangement makes the hormones secreted from each cell, which affects the function of other cells [13,14]. Further studies have shown that paracrine effects may play an important role in regulating hormone secretion. The way of blood supply to the islets of Langerhans also confirms the paracrine regulation of hormone secretion. In this way, the afferent blood vessels penetrate the center of the islet first, and therefore, the innermost cells of the islet receive arterial blood, while the external cells receive blood containing the secretions of internal cells [15,16]. Therefore, due to the special arrangement of cells in the islets of Langerhans, the central cells can regulate the secretion of the outer cells. In addition to the paracrine system, the autonomic nervous system is also effective in regulating the secretion of pancreatic hormones. Islet cells receive sympathetic and parasympathetic nerves and regulate hormone secretion in response to nerve input [17,18].

Beta cells, as one of the most abundant types of endocrine cells, are mainly localized in the central space of each islet and secrete insulin and amylin hormones [19]. Insulin, as the most well-known hormone produced only by beta cells, plays an important role in regulating the body's metabolism and glucose homeostasis. Release of this hormone is regulated by various factors including hormones and blood glucose. The pancreatic blood vessels originate from the splenic artery. Therefore, the islets are exposed to the systemic concentration of blood glucose and release insulin in response to hyperglycemic conditions [20].

Alpha cells as the second most abundant endocrine cells form a cortical layer at the periphery of the islets. In human pancreas, more than 90% of alpha cells are in direct contact with beta cells and their secretion is regulated by various factors including hormones, autocrine, and paracrine mechanisms [21]. Alpha cells express proglucagon gene and produce glucagon hormone, which is involved in regulating blood sugar. Proglucagon gene is also expressed in brain and intestinal L-cells and processed into various molecules including glucagon-like peptide-1 (GLP-1) and GLP-2 that implicated in glucose homeostasis [22,23].

Delta cells are generally located between the beta and alpha cells in the periphery of islets. Delta cells as well as hypothalamic cells produce somatostatin hormone, which reduces the secretion of various hormones including insulin, glucagon, gastrin, and growth hormone [24].

F cells as the least abundant hormone-producing cells constitute lower than 1% of the total islet cells. F cells produce and release pancreatic polypeptide (PP) that regulates the exocrine and endocrine secretion activities of the pancreas. The secretion of PP was shown to be negatively regulated by various factors including somatostatin and bombesin. Recent findings indicate that PP decreases secretion of gastric acid and attenuates intestinal motilities that enhanced the intestinal transit time [25,26].

1.2.2 Exocrine pancreas

Pancreas consists of two separate functional parts, exocrine and endocrine, which are involved in digestion and glucose homeostasis. The exocrine part of the pancreas, which constitutes 84% of the total pancreas mass, contains acinar and duct cells that participate in the intestinal digestion of nutrients (Fig. 1.2) [27]. Acinar cells (or acini) are the most abundant pancreatic cells that produce several types of active or inactive enzymes including amylase, lipase, trypsinogen, and chymotrypsinogen, which are released and activated in the duodenum [28]. The duct cells produce an alkaline, bicarbonate-rich fluid, which is secreted in the duodenum. In fact, the duct system, in addition to functioning as a conduit for pancreatic juice, stabilizes the exocrine proenzymes by changing the composition of pancreatic secretions by releasing bicarbonate, water, and sodium chloride [29].

Figure 1.2 Exocrine acinar and ductal cells.

1.3 Pancreas cancer pathology

Pancreatic cancers are classified based on their biological behaviors into benign and malignant tumors. According to histological differentiation, pancreatic neoplasms are classified into epithelial or nonepithelial types. Epithelial cancers can be divided into neoplasms with endocrine and exocrine differentiation [30]. Here, we present the main pathological features of exocrine tumors including pancreatic ductal adenocarcinoma (PDAC), acinar cell carcinoma (ACC), pancreatoblastoma, and endocrine tumors.

1.3.1 Pathology of the exocrine neoplasms of the pancreas

The term exocrine pancreatic neoplasms includes all malignancies associated with the pancreatic ductal and acinar cells [31]. More than 95% of malignant pancreatic cancers originate from the exocrine cells, which are listed in Table 1.1.

Table 1.1

The pancreatic exocrine neoplasms are staged by the tumor, node, and metastasis (TNM) classification of the American Joint Committee on Cancer as presented in Table 1.2.

Table 1.2

TNM, Tumor, node, and metastasis.

1.3.1.1 Pancreatic ductal adenocarcinoma

PDAC is the most aggressive tumor of the exocrine cells and contributes to about 90% of all pancreatic malignancies [32]. PDAC is often formed in the head of pancreas, but less frequently in the body or tail. Surgical resection and adjuvant chemotherapy are the only curative methods for 10%–20% of PDAC patients, while most patients are unresectable because they have either invaded nearby organs or had distant metastases [33]. PDAC metastasis can occur in any organ at various distances including liver, lung, skin, and adrenals. It has been shown that several risk factors are associated with the occurrence of PDAC including chronic disease, environmental, and genetic factors [34–36]. In addition, recent findings indicate that many cases of PDAC may originate from noninvasive epithelial precursor lesions including pancreatic intraepithelial neoplasias (PanINs). Therefore, detection of these epithelial lesions may provide an opportunity for preventing PDAC development or reducing cancer-related mortality [37,38].

The majority of PDAC patients suffer from nonspecific symptoms including abdominal pain, diarrhea, vomiting, and weight loss. Upon the tumor progression, the pancreas and bile ducts are closed resulting in alleviated bile and pancreas secretion into the duodenum. In this condition, the absorption of food and fat is reduced and weight loss occurs. The most common symptom of PDAC is jaundice, which occurs when a tumor grows in the head of the pancreas and blocks the bile duct [39]. Moreover, PDAC causes defects in the function of pancreatic beta cells, resulting in diabetes mellitus [40]. Considering that a large part of PDAC patients have impaired insulin secretion, the possibility of PDAC should also be considered in differential diagnosis with respect to type 2 diabetes [41]. The prothrombin time was also increased in PDAC due to reduced absorption of fat and vitamin K [42].

1.3.1.2 Acinar cell carcinoma

ACC is an uncommon malignant epithelial neoplasm that is mostly diagnosed in men at the age of 60 years or older. ACC can occur in any part of the pancreas but is more common in the head [43]. AAC are characterized by their morphological similarity to acinar cells and releasing pancreatic exocrine enzymes including trypsin, chymotrypsin, and lipase. Therefore, immunostaining for detection of these pancreatic digestive enzymes is very useful for confirming the diagnosis of acinar cell neoplasia [44].

1.3.1.3 Pancreatoblastoma

Pancreatoblastoma is a rare epithelial malignancy that originates from the exocrine cells of the pancreas. Pancreatoblastoma occurs in all areas of the pancreas, including the head, body, and tail with equal frequencies. Pancreatoblastoma shows acinar differentiation and therefore mimics AACs, but pancreatoblastoma occurs in children and ACC occurs in adults. In addition, the squamoid nests in pancreatoblastoma are the distinguishing feature for the correct diagnosis of pancreatoblastoma [45]. The vast majority of pancreatoblastoma has been identified in children with a mean age of 5 years. This type of tumor is slightly more common in men and two-thirds of existing tumors are reported from Asian patients. Pancreatoblastoma rarely occurs in adults and the prognosis is worse in adults than in children [46,47]. One of the clinical manifestations of pancreatoblastoma is the increase of α-fetoprotein levels, which can be used to monitor the response to treatment [48]. Moreover, patients with pancreatoblastoma display loss of chromosome 11p, which has been reported in other infantile cancers including hepatoblastoma [49].

1.3.2 Pathology of the endocrine neoplasms of pancreas

Pancreatic endocrine neoplasms are mainly malignant neoplasms, accounting for about 5% of all pancreatic tumors. These neoplasms are epithelial tumors with endocrine differentiation, which can be located in any portion of the pancreas. Pancreatic endocrine neoplasms may arise at any age group but are most commonly diagnosed between the ages of 50 and 60 years [50,51].

Pancreatic endocrine neoplasms are classified into functional or nonfunctional categories depending on their ability to secrete specific hormones and to cause characteristic symptoms. Nonfunctional neoplasms secrete molecules, such as chromogranin, neuron-specific enolase, PP, and ghrelin, and do not cause clinical manifestations related to hormone secretion [52,53]. The classification of pancreatic endocrine neoplasms is presented in Table 1.3.

Table 1.3

In addition, according to the type of released hormone, various functional neoplasms are diagnosed including insulinoma, gastrinoma, and glucagonoma (Table 1.4). These functional neoplasms may appear with symptoms related to excessive hormone secretion [54].

Table 1.4

Insulinoma is the most frequent tumor of pancreatic endocrine cells, 90% of which are benign. However, 10% of insulinomas occur as part of multiple endocrine neoplasia type I (MEN-I) syndrome [55]. The most important symptom of insulinoma is hypoglycemia, and its related complications include headache, visual disturbances, seizures, and death in severe cases. The gold standard for the diagnosis of insulinoma is a monitored 72-hour fasting test with measurements of plasma glucose, insulin, C-peptide, and proinsulin at the onset of hypoglycemic symptoms [56,57].

Gastrinoma is one of the most common functional and malignant pancreatic endocrine tumors that release large amounts of gastrin, which leads to hyperplasia of parietal cells and increases gastric acid secretion [58]. Excessive output of stomach acid damages the mucosal defense of the stomach and causes severe peptic ulcer disease and diarrhea, which is referred to as Zollinger-Ellison syndrome. Gastrinoma is usually diagnosed between the ages of 20 and 50, which is more common in men. The diagnosis of gastrinoma is confirmed through an increase in the fasting serum gastrin concentration associated with an increase in the secretion of gastric acid or low gastric pH [59].

Glucagonoma is a rare alpha-cell tumor in the Langerhans islets, which is mainly located in the pancreatic tail. This endocrine neoplasm secretes glucagon and causes various symptoms including hyperglucagonemia, diabetes mellitus, anemia, weight loss, and diarrhea. Fasting plasma glucagon greater than 500 pg/mL can be used as a diagnostic tool for glucagonoma [60].

VIPoma is another rare pancreatic endocrine neoplasm that secretes vasoactive intestinal polypeptide (VIP). VIPoma is usually located in the body and tail of the pancreas [61]. The major clinical signs of VIPoma are watery diarrhea, hypokalemia, and metabolic acidosis [62]. VIPoma and its related symptoms are known as Verner-Morrison syndrome or pancreatic cholera. A serum level of VIP greater than 200 pg/mL may be used for the diagnosis of VIPoma [63].

Somatostatinoma, as a curious endocrine neoplasm, originates from pancreatic delta cells and produces somatostatin hormone. Increased secretion of somatostatin inhibits several gastrointestinal hormones and causes a triad of symptoms of somatostatinoma including diabetes mellitus, cholelithiasis, and steatorrhea. Increased blood levels of somatostatin can serve as a specific biomarker for tumor follow-up [64,65].

As shown in Table 1.3, a PP-secreting tumor (PPoma is a nonfunctional neoplasm that makes up approximately 50% of neuroendocrine tumors of pancreas). PPoma secretes pancreatic polypeptide and causes various nonspecific symptoms including weight loss, abdominal pain, jaundice, and diarrhea [66].

Most patients with nonfunctional endocrine neoplasms are identified with a number of nonspecific symptoms including bellyache, enlarged liver, jaundice, and obstruction of the pancreatic duct. Therefore, nonfunctional neoplasms may be diagnosed with a larger size, higher metastatic rate, and worse prognosis. Similarly, PPoma demonstrates a lower overall survival than functional neoplasms. Considering that nonfunctional neoplasms have a better prognosis than pancreatic exocrine tumors, it is very important to differentiate between a nonfunctional tumor and a functional pancreatic neoplasm [52,67].

1.4 Conclusion

Pancreatic cancer represents a challenge for identifying novel diagnostic and prognostic biomarkers. Despite recent efforts to improve the screening, diagnostic, and therapeutic methods, patients with pancreatic cancer exhibit dismal prognoses and lower survival rates. A complete understanding of the clinical symptoms related to the types of pancreatic malignancies has a central role in the correct diagnosis and treatment of patients with pancreatic cancer. In addition, the widespread use of novel methods of gene and protein analysis plays an important role in recognizing the type of neoplasm and determining the correct treatment method.

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Chapter 2

Different combination therapies pertaining to pancreatic cancer

Zahra Salmasi¹*, Parisa Saberi-Hasanabadi²*, Hamidreza Mohammadi², ³ and Rezvan Yazdian-Robati³,    ¹Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran,    ²Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran,    ³Pharmaceutical Sciences Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran

Abstract

Pancreatic cancer (PC) is considered one of the lethal malignancies worldwide with a poor prognosis and a median survival rate of 10% in affected persons in a period of several years (about 5 years). Despite recent advancements, effective treatment for PC has remained elusive. A potentially more serious problem is that monotherapies usually cause the intensification of drug resistance with the low effectiveness of the active substance and also metastasis or recurrence of the tumor after the chemotherapy process. A potential way to make the treatment process more effective and decrease side effects is using the combination or multicomponent treatment approach. Codelivery systems along with different therapeutic nanoplatforms lead to an increase in desired response or achieving synergistic-combination results compared to a single drug strategy. Recently, multidrug combination therapy along with the nano-structures of the smart drug delivery systems to PC therapy is widely applied in clinical practice.

In the current chapter, a concise description of some different modes of multidrug combination therapy, including the design of formulations containing natural compounds along with conventional anticancer drugs in different nano-carriers were introduced. This study can be considered an encouraging and potential approach to PC treatment with minimizing the adverse effects associated with conventional chemotherapy.

Keywords

Pancreatic cancer; multidrug combination therapy; drug delivery systems; different therapeutic nanoplatforms; natural compounds

2.1 Introduction

Pancreatic cancer (PC) is one of the silent cancers that progresses quietly and its symptoms appear in the final stages. This disease is one of the most fatal and aggressive cancers, which annually has more than 330,000 deaths. Men are at greater risk for PC than women [1]. Pancreas is one of the organs of the digestive system, which, along with the gallbladder, plays an important role in food digestion. Some mutations in the DNA of the pancreatic cells lead to continuous cell proliferation, which disrupts the apoptosis process and cell death that cause tumor formation. If the cancer is not treated, it spreads to the surrounding organs and blood vessels [2]. PC diagnosing can be difficult because there are no obvious symptoms at the beginning of pancreatic malignancy. But in people with pancreatic cysts or with a family background of PC, cancer screening helps in early detection [3]. To date, surgery is known as one of the earliest forms of cancer therapy. After surgery, the next standard of care is radiotherapy and chemotherapy. Most pancreatic tumors cannot be surgically removed due to metastasis and invasion of the main posterior vessels of the pancreas. Radiation combined with chemotherapy is used to slow down the progression of locally advanced cancers. Abraxane, Afinitor, everolimus, 5-FU, gemcitabine hydrochloride, gemzar, and nano-encapsulated form of bioactive compounds such as curcumin are among the most common effective chemotherapy agents for the treatment of PC [4]. Usually, there is a connective tissue called stroma around pancreatic tumors. The stroma is like a protective shield that prevents the effect of chemotherapy drugs. To solve this problem, chemotherapy drugs must be persistent so that they can pass through the stroma and reach the tumor. On the other hand, the long shelf life of the drug can poison healthy tissues and blood and be harmful to the patient. Therefore, we need to use high amounts of medicine and repeat the drug treatment many times, which along with the intensification of drug resistance will lead to an increase in side effects [5]. To overcome these limitations, it seems that the use of combined treatment is a suitable solution. Combination therapy, polytherapy, or multimodal treatment, all refer to the application of two or more types of treatments that are used in a different manner: simultaneously, in order, or at different times [6]. Combination drug therapy may be achieved by prescribing separate drugs in a fixed dose or in a medicinal form containing more than one active ingredient. In some cases, for detecting the best drug formulation, patients have to try several different combinations of drugs [5]. Since a pathogen or tumor is less likely to be resistant to multiple drugs simultaneously, therefore, reduction of drug resistance is considered one of the most important benefits of combination therapy [6]. In the short period of treatment, combination therapy may seem costs more than monotherapy but actually, when this treatment approach is used properly, it will save significantly during the treatment. Fewer failure rates during treatment, lower mortality, fewer side effects, less drug resistance, and, as a result, reduction in costs are among the important advantages of combination therapy usually, the main goal of developing codelivery platforms is to achieve a combination of different treatment mechanisms. Along with conventional methods, including surgery, radiation, and chemotherapy, other treatment strategies such as gene therapy, photodynamic therapy, photothermal therapy, and immunotherapy can be used in tumor treatment and seems to be more beneficial than one method alone [7,8]. In special conditions, combination therapy can not only attain a higher probability of success than monotherapy but also can do with less adverse effects on normal cells [9]. The combination of radiation and chemotherapy along with controlled drug delivery vehicles may destroy cancerous tissue without losing the organ containing the tumor [8]. The advantages of the last option compared to single drug treatment are: (1) Optimal design in line with better synergistic effects and avoiding the single use of more drugs together, (2) Optimizing patient compliance, and, (3) Accurate monitoring of individual doses and avoidance of uncertainty due to divisibility of drug doses. In this regard, coadministration of common medicinal compounds along with active ingredients of natural origin is another attractive strategy considering the general safety of phytotherapy [10–12]. For example, quercetin has received special attention in recent studies as a polyphenolic flavonoid but, unfortunately, its clinical application is limited due to inherent lipophilicity, instability in the circulation, and low bioavailability [13]. For this reason, the use of nano-carriers in combination with nanoplatforms has been considered. Some advantages of this approach are as follows: desirable biological structures, increased serum consistency, controlled medications release, high carrying capacity, long-term systemic circulation, decreased nonspecific cellular uptake, optimized selection of anticancer drug compounds to tumor tissue by increasing permeability and retention time, and ability of multidrug encapsulation for combinatorial treatment [14–16]. In this chapter, we collected the results obtained from the recent studies in developing different methods of combination therapy and their applications in PC