Molecular Pharmaceutics and Nano Drug Delivery: Fundamentals and Challenges

By Umesh Gupta

Molecular Pharmaceutics and Nano Drug Delivery: Fundamentals and Challenges provides a thorough resource for both beginners and established scientists, bringing fundamental knowledge about key challenges of these carriers down to the molecular level. The book satisfies the need of availability of literature at single platform with the detailed knowledge to understand crucial aspects, such as regulatory, clinical, toxicological and the formulation requirements of these carriers. This is a valuable resource for graduates, pharmaceutical researchers and anyone working on aspects of pharmaceutics, molecular pharmaceutics and nano-drug/gene delivery.

So called ‘novel drug delivery systems’ are numerous, with each having different approaches to their production, characterization and evaluation. The proper understanding of these dosage forms, as well as their critical attributes such as toxicity and regulatory requirements are aspects which researchers should know before they begin working on these carriers. This book provides this critical information.

• Provides a conceptual understanding of Molecular Pharmaceutics and drug/gene delivery systems of biological origin
• Presents a detailed description and discussion on nanotechnological carriers, from basics to advances, including gene delivery and protein-oriented delivery
• Includes regulatory and toxicological requirements for novel drug delivery systems

• Language: English
• Publisher: Academic Press
• Release date: Oct 17, 2023
• ISBN: 9780323914154

Book preview

Preface

Umesh Gupta and Amit K. Goyal

Molecular pharmaceutics deals with the science of dosage forms and formulation design. It is the major area of pharmaceutical sciences, which focuses and emphasizes on the technological aspects of how a new chemical entity is converted into a suitable dosage form and subsequent formulation. Traditionally, the tablets, capsules, syrup, solutions, and ointments were the most popular dosage forms for delivering drugs to patients for different ailments. However, in the last few decades, the introduction of novel dosage forms has completely shifted the traditional paradigm of drug delivery technologies. The so-called novel drug delivery systems are numerous, and each has different approaches with respect to their production, characterization, and evaluation. Some of these are at the laboratory levels, while some of these have successfully made their way into the market. A proper understanding of these dosage forms as well as their critical attributes such as toxicity and regulatory requirements are some of the aspects which researchers should know before starting to work on these carriers. Individual literature is available at discrete levels for each of these novel drug carriers such as liposomes, nanoparticles, niosomes, phytosomes, dendrimers, quantum dots, and carbon nanotubes. This book is an attempt to provide fundamental information to readers, from a beginner to an established scientist, on the key challenges of these carriers at the molecular level. This book satisfies the need for availability of literature in a single platform with the detailed knowledge to understand the crucial aspects such as regulatory, clinical, toxicological, and formulation requirement of these carriers. This book will help the readers to design and develop novel drug delivery systems and devices for the treatment of different disorders by taking advantage of recent advances in nanomedical technologies.

This book is a fair attempt to address the basic aspects of molecular pharmaceutics as well as nano drug delivery through different chapters. This book comprises 14 chapters: Protein and Enzyme-Based Formulations; Vaccine and Sera; Aptamers and Antisense Oligonucleotide-Based Delivery; Monoclonal Antibodies: Recent Development in Drug Delivery; Hormonal Delivery Systems; Vesicular Drug Delivery Systems: a Novel Approach in Current Nanotherapies; Polymeric Micelles in Drug Delivery and Targeting; Physicochemical Characterization of Drug Delivery Systems Based on Nanomaterials; Inorganic and Metal-based Nanoparticles; Dendrimers: Promises and Challenges in Drug Delivery; Development of the Different Advanced Diagnostic Platform for Detection of Infectious Diseases; Fundamentals of a Targeted Drug Delivery System; Toxicological and Regulatory Aspects of Nanomaterials: Recent Updates; and Gene Therapy: Advocacies, Perspectives, and Ethical Provocations.

Chapter 1

Protein and enzyme-based nanoformulations

Biswakanth Kar, Deepak Pradhan, Prativa Biswasroy, Jitu Haldar, Tushar Kanti Rajwar, Vineet Kumar Rai, Goutam Ghosh and Goutam Rath,    School of Pharmaceutical Science, Sikhsa O Anusandhan University, Bhubaneswar, Odisha, India

Abstract

Protein drug delivery has significantly impacted the treatment of various important human diseases, including cancer, diabetes, and hypertension. Protein therapies provide advantages over conventional small-molecular medications, which continue to rule the pharmaceutical industry. These advantages include higher specificity, more significant activity, and lower toxicity. However, proteins' excellent specificity frequently necessitates keeping their structural complexity, making them challenging to alter. Moreover, there are considerable obstacles to the efficient transport of specific therapeutic proteins (such as enzymes and cytokines) to specific disease locations due to their sensitivity to enzymatic breakdown, short circulation half-lives, and low membrane permeability. Nanotechnology has shown numerous applications for protein delivery, and many more are now being tested in real-world settings. Particularly, nanoparticles, including lipidic nanoparticles, polymer nanoparticles, and inorganic nanomaterials, have significant benefits as drug carriers for protein delivery. It plays an important role in improving the difficulties mentioned above for protein delivery. In this chapter, we briefly discussed the nanocarrier systems for the delivery of protein and enzymes and highlighted the advantage of their applications for improved functionality. Also, we discussed the various challenges associated with protein delivery.

Keywords

Protein drug delivery; challenges; nanotechnological approaches

1.1 Introduction

In several biological processes, such as catalysis, transport, gene expression control, immunity-related activities, and so forth, proteins and enzymes are essential. Additionally, they play a role in various clinical disorders, including cancer, diabetes, and hypertension [1]. Proteins are desirable therapeutic agents for treating many diseases due to their wide variety of functions and their involvement in diseases. The first commercially available recombinant therapeutic protein was human insulin, which was approved by the US Food and Drug Administration (FDA) in 1982 [2]. Since then, it has replaced other treatments as the primary option for those with type I and types II diabetes. There are currently more than 100 authorized peptide-based medications on the market [3]. The market for protein and peptide pharmaceuticals is expanding significantly more quickly than for small molecule pharmaceuticals. Notably, since the approval of Muromonab-CD3 in 1986, monoclonal antibodies (mAbs) have represented a promising area of protein therapy research. One of the most exciting developments in cancer immunotherapy is the recent clinical validation of immune checkpoint mAbs that target the programmed death-1 (PD-1) receptor, such as Nivolumab and Pembrolizumab [4]. Compared to small-molecule drugs, these therapies have several benefits, including high potency, activity, reduced unspecific binding, decreased toxicity, minimal drug–drug interactions, and biological and chemical diversity. However, proteins' physicochemical characteristics make their application as medications challenging. First, oral administration of proteins and peptides is unsuitable due to their instability in the gastrointestinal tract. Its usefulness is constrained by physical and chemical degradation, a short in vivo circulation half-life and biodistribution, and the lack of an effective, secure, and targeted administration mechanism. Their ability to penetrate cell membranes and be cleared by mononuclear phagocytes of the reticuloendothelial system, as well as the possibility of an immunogenic reaction, solubility problems, high molecular weight, and structural complexity, all reduce the effectiveness of their treatments. Therefore, to achieve high therapeutic efficacy, it is necessary to establish appropriate delivery platforms for proteins and enzymes [5]. Over the past few decades, significant research has been conducted to develop protein and peptide delivery systems that get around the issues outlined above. Numerous methods have been used to achieve this goal, including mucoadhesive polymers, enzyme inhibitors, absorption enhancers, nanoparticle carriers, and chemically altering protein or peptide structures. Among these, nanocarrier systems demonstrated a tremendous application for the delivery of proteins. Particularly, nanoparticles with sizes typically between 10 and 30 nm, including liposomes, micelles, polymer nanoparticles, and inorganic nanomaterials, have significant benefits as drug carriers [6]. Generally, nanoparticles aggregate to reduce surface energy. After being systemically delivered, these aggregates and the surface properties of the particles, such as charge and hydrophobicity, can lead to opsonization in the blood, which increases the visibility of nanoparticles to biological defense systems like the mononuclear phagocyte system and exposes them to removal from circulation by defense cells, significantly reducing their effectiveness [7]. For example, Wu et al., in 2014, prepared LGA–polycation nanoparticles for encapsulation and delivery of protein bioactive for sustained release of proteins while maintaining protein bioactivity. They reported that nanoconjugate systems effectively interact with proteins with high protein loading (20–40 wt.%) [8]. The nanotherapeutic approach enhanced the circulation half-life, biodistribution, and targeted delivery of intracellular-acting protein. Kim and a coworker developed a nano composed of lipid and apolipoprotein for targeted delivery to the lung cancer cell. The resulting nanocomposite with a particle size of 20–30 nm showed 64%–75% loading efficiency and exhibited significant apoptosis in H460 cells [9]. Numerous nanomedicines for protein delivery have already received clinical approval, and many more are undergoing clinical trials. For example, the FDA approved pegaptanib in 2004 [10], an RNA oligonucleotide aptamer that specifically binds to the angiogenic vascular endothelial growth factor protein. After a year, the FDA approved Abraxane1, an albumin-bound nanoparticle formulation of paclitaxel that boosts albumin delivery to tumor cells by encouraging receptor-mediated trans-cytosis. This chapter provides a brief overview of the nanocarrier systems for the transport of proteins and enzymes and emphasizes the benefits of their use in enhancing functionality. We also go over the numerous difficulties with protein delivery.

1.2 Challenges associated with protein and enzymes delivery

Proteins and peptides are the preferred drugs for treating a variety of disorders due to their powerful and efficient actions. Protein delivery research priorities include creating appropriate target-specific protein carriers and stabilizing proteins in delivery devices. Due to its fragility, complexity, higher molecular weight, protein denaturation, and changing spatial properties, the distribution of proteinaceous drugs has presented significant challenges for pharmaceutical and biomedical research. The success of developing carrier systems hinges on their capacity to preserve protein activity and structure during the development process, throughout delivery to the targeted region, and during long-term storage [11]. Improved protein stability is required for the delivery of therapeutic proteins. Despite significant advancements in the mass production of therapeutic proteins, it is still difficult to deliver these medications to the body in a way that is both practical and efficient. The challenges that proteins and peptides face by different routes of administration are summarized in Table 1.1. Although the oral route for the delivery of therapeutic peptide and protein therapeutics has been studied for decades, additional routes, including the nasal, pulmonary, ophthalmic, buccal, and transdermal routes, are also being investigated today [12].

Table 1.1

Additionally, an intriguing membrane that limits the majority of hydrophilic molecules is the blood–brain barrier. Endothelial cells that surround the brain capillaries provide this barrier, which is supported by numerous cells such as pericytes, astrocytes, and microglial cells. This barrier’s function is to protect the brain from harmful substances, germs, and toxins, while maintaining the brain’s homeostasis [13]. For this purpose, the cerebral endothelium is outfitted with very tight junctions that significantly restrict the movement of water and polar solutes across the membrane, as well as highly effective efflux systems made up primarily of organic anion transporters and transporters from the ATP binding cassette (ABC transporters) (OAT). The LRP1, transferrin, insulin, and amino acid receptors or transporters are a few examples of transporters that are used to move necessary substances across the blood–brain barrier. Some substrates can also be transported into the brain by OAT. However, the majority of therapeutic medicines, particularly macromolecules, cannot enter the brain through the bloodstream, the aforementioned transporter systems virtually always reject lipophilic compounds, and tight junctions prevent the transport of hydrophilic chemicals [14]. As per Galliani et al., in 2018, the systemic administration of proteins and large molecules suffers from degradation majorly, poor biodistribution, and inability to cross most biological barriers that severely affect the efficacy of protein and enzyme replacement therapies for many diseases, in particular for those involving the central nervous system [15].

1.3 Nanocarrier system for protein and enzyme delivery

The use of proteins as therapeutics has increased in the healthcare industry to treat several disease conditions because it helps to create potentially specialized medicines. Instability, short half-life, and immunogenicity frequently limit their safety and effectiveness. Nanocarriers have the potential to improve protein delivery as therapeutics. The nanotherapeutic approach can overcome these limitations by increasing the systemic circulation half-life of protein, by protecting proteins from premature degradation, denaturation, and release. Additionally, nanotechnology helps targeted delivery of proteins with controlled or sustained release [16].

1.3.1 Polymeric nanocarrier system

Protein–polymer conjugates have been shown to have a unique combination of characteristics from both materials (i.e., the protein and the polymer), which can be individually modified to produce acceptable effects as a treatment strategy. Several works have been done for protein delivery through a nanotherapeutic approach. For example, Rebekah et al. prepared a magnetic nanoparticle-decorated graphene oxide-chitosan composite as an efficient nanocarrier for bovine serum albumin (BSA) delivery and studied its activity and stability performance. The result showed enhanced drug loading and better release profile compared to the free drug. Also, the nanocomposite protects the protein from enzymatic degradation [17]. Protein transportation through nanocarriers has been used in different disease conditions. Zhang and colleagues developed a zwitterionic chitosan-based nanocarrier for the pulmonary delivery of therapeutic proteins for treating pulmonary lungs. The ionic gelation method was used to load the antifibrosis therapeutic protein (msFGFR2c), into a zwitterionic nanocomplex. Results showed after orotracheal administration, the nanocombination can inhibit the transforming growth factor beta 1-induced α-smooth muscle actin expression, responsible for fibroblasts, while the naked protein showed poor efficacy [18]. In another study, Xie and group developed a customized nanocarrier for interleukin 10 plasmid (pIL-10) delivery. The novel carrier improved muscle repair outcomes and biocompatibility in several acute muscle damage mouse models. The novel carrier had the potential for safe nuclear acid delivery in vivo to treat numerous muscle disorders [19]. Nanocarrier systems also help to deliver protein biomolecules through the oral route. Lee and coworkers developed a zonula occludins toxin-derived peptide and chitosan-functionalized pluronic-based nanocarrier for enhanced transepithelial transport of insulin orally, both in vitro and in vivo. For effective oral delivery of insulin, the protein must be shielded from gastric and enzymatic destruction, allowed to persist on the intestinal surface for an extended period to improve protein absorption, and successfully penetrated through the tight epithelial junction. Only chitosan functionalization can boost the mucoadhesive property of the nanocarriers in the small intestine, but it is unable to go beyond the small intestine wall’s absorption barrier. Contrarily, dual functionalization with chitosan and peptide permitted extended small intestine residence as well as efficient junction penetration. As a result, the synergistic effect of the dual targeting of nanocarrier showed the largest reduction in blood sugar level after 12 hours of oral administration [20].

1.3.2 Lipidic nanocarrier system

Fatty acids, fatty alcohols, phospholipids, long and medium-chain monoglycerides, diglycerides, and triglycerides are among the natural, semisynthetic, or synthetic lipids utilized to create lipid-based nanoparticles. Dietary fats or oils are used to make the majority of lipid excipients. Because of their biocompatibility, biodegradability, low toxicity, and ability to pass through a variety of biological barriers (including digestive fluids, mucus layer, and intestinal epithelium), lipid nanoparticles are thought to be a promising protein delivery technique [21].

Csiszar and coworkers developed fusogenic liposomes for intracellular protein delivery ranging in size from 2.3 to 240 kDa (R-phycoerythrin). In general, interactions between proteins or peptides and liposomal components like lipids, surfactants, polymers, or inorganic compounds have a significant impact on how well they are encapsulated and how quickly they are released. These elements, which are connected on the liposomal surface, may improve the stability of nanocarriers, regulate the drug release period, and encourage protein distribution at the desired location [22].

It has been discovered that programmable cell death is dysregulated in a number of diseases, and the ability of cells to evade it is a defining characteristic of cancer. The mitochondrion is a strong candidate for anticancer treatment in this case. The essential outer mitochondrial membrane (OMM) component voltage-dependent anion channel (VDAC) regulates connections and communication between mitochondria and other cell compartments. Liguori and coworkers described an optimized cell-free production of a pivotal protein (VDAC), directly into liposomes for integration with biomimetic membrane systems. A supported lipid bilayer membrane that enables electrical evaluations of the ionic conductance of integrated membrane proteins was combined with a cell-free expression method to construct a functioning VDAC. The main benefit is in the analysis of the pure VDAC protein’s properties to identify particular impacts to support, examine, and comprehend the various membrane pathways that VDAC affects in the cell. Additionally, because membrane proteins are a main target for therapeutic drugs, we can increase the number of transporters, channels, and exchanger proteins created by cell-free methodologies so they can be integrated into the connected membrane for the creation of biomimetic tools like biosensors or diagnostic tools [23].

There has been a lot of interest in the targeted intracellular delivery of medicines to boost biological activity during the past few decades. There are many different kinds of biomaterials, and it is well known that employing them to treat serious diseases has advanced significantly. Protein-based therapeutic materials are widely used for the treatment of a variety of illnesses like cancer, diabetes, and inflammatory diseases in the medical industry. By altering liposomes by adding hydrophobic polyampholytes within, Matsumura et al. created a novel protein delivery carrier. The adsorption and internalization of protein-incorporated polyampholyte liposomes were improved after freezing compared to that seen in unfrozen complexes, according to flow cytometry and microscopic examination. Studies on inhibition showed that polyampholyte-modified and unmodified liposomes have different internalization mechanisms. Additionally, polyampholyte-modified liposomes demonstrated high efficiency in promoting endosomal escape to improve protein transport to the cytoplasm with minimal damage [24].

Another type of lipidic nanocarrier is solid lipid nanoparticles (SLNs), which have been considered as a promising technology for delivering genes and proteins due to their exceptional biodegradability and biocompatibility, ability to perform a specific function through the appropriate chemical modification, and speedy uptake by cells [25].

Oral administration of insulin as a noninvasive treatment for diabetes mellitus is currently impractical because of its high molecular weight and lack of lipophilicity, as well as its quick enzymatic deterioration in the stomach, slight decrease and metabolism by enzymes in the intestinal lumen, and poor permeability throughout the intestinal epithelium. Oral insulin, however, has an advantage over endogenous insulin, in that it is transported to the liver, which is where it works most effectively via portal circulation. Zahang and group designed and characterized SLNs of insulin, modified with stearic acid–octaarginine (SA-R8), to improve the stability and bioavailability for oral administration. According to the result, SLNs and SA-R8 were able to partially shield insulin from proteolysis in an in vitro enzyme degradation experiment. The prepared SLNs boosted Caco-2 cell internalization up to 18.44 times the normal insulin solution. In vivo tests on diabetic rats revealed a significant hypoglycemic impact compared to controls with prepared SLNs. These findings showed that SA-R8-modified SLNs facilitate the absorption of insulin orally [26].

The challenge of enhancing protein therapeutic bioavailability persists despite the recent focus on oral protein delivery. The gastrointestinal enzymatic barrier and the absorption barrier, which are composed of mucus layer and intestinal epithelial cells, must be broken down in addition to the negative physicochemical effects of drugs. The salmon calcitonin-loaded SLNs are synthesized and characterized by Huang and colleagues using the affinity peptides CSKSSDYQC (CSK) and CPP IRQRRRR (IRQ) for goblet cells. Studies conducted in vitro and in vivo revealed that the modified SLNs with peptides altered the internal accumulation of protein therapeutics on Caco-2/HT29-MTX co-cultured cells and penetration in excised rat duodenal mucosa. The protein can also be changed with functional ligands to improve the therapy of diseases, in addition to altering the lipids surface to improve the targeted protein delivery [27].

1.3.3 Inorganic nanocarrier systems

Proteins are biomacromolecules with therapeutic value, but due to large size and shape, protein molecules cannot penetrate the cell membrane. Inorganic nanoparticles have the potential to overcome the barriers associated with delivery of proteins and protein-based drugs to different cells [28]. Inorganic nanoparticles like metal nanoparticles, silica nanoparticles, graphene oxides, silica nanoparticles, magnetic nanoparticles, and so forth are used for delivery of protein molecules and protein-based drugs [29]. Recently, aquasomes have emerged as an efficient drug delivery system for proteins and peptides. Aquasomes are self-assembled nanostructures consisting of a spherical hydroxyapatite inner membrane and carbohydrate at the outer membrane, which absorb proteins and penetrate the cellular barriers [30]. Damera et al. showed that aquasomes are used as the intracellular delivery system for BSA along with hydrophobic drugs warfarin (War), Ibuprofen (Ibu), and Coumarin (C153). Experimental findings showed that ~30% of BSA released from the aquasomes after 120 hours in a sustained release manner. Also, it has been found that aquasomes-encapsulated BSA and hydrophobic drugs showed improved biocompatibility and low hemolytic activity [31]. Similarly, Omar et al. found that biodegradable Magnetic silica @Iron oxide nanovectors have potency to deliver large proteins (diameter above 15 nm). It has been found that prepared magnetic hybrid nanovectors are potential candidates to deliver large proteins (~534 kDa, HD~20 nm) inside the cancerous cells. Also, it has been reported that large-scale cavities of prepared nanovectors provide electrostatic immobilization to large proteins up to 23 wt.% [32]. Among various nanoparticles, quantum dots (QDs) have shown distinct benefits in bioimaging, biosensing, and drug delivery compared to any other nanoparticles due to their particular photostability and photochemical features, QDs, among other metallic nanoparticles. Dynamic processes, temperature, and QDs' size are the key determinants of their photochemical characteristics. Zhao and coworkers prepared a pH-activated charge-convertible QD as a novel nanocarrier for targeted protein delivery and cancer cell imaging. According to experimental findings, the complex provided legible real-time imaging for lung cancer cells and demonstrated improved internalization and quick endo/lysosomal escape. Additionally, the complex killed cancer cells more efficiently than the control groups did due to its pH-triggered charge-convertible ability [33] (Table 1.2).

Table 1.2

1.4 Conclusion

There are numerous uses for nanoparticles in both industry and medicine. They can be utilized as medicines or as carriers of therapeutic compounds depending on their physical and chemical characteristics. Protein delivery through the use of nanocarriers might lessen undesired restrictions and lower the dosage of drug required to produce the desired therapeutic effect. In order to prevent the medicine from degrading, extend its time in the body, and lessen its toxic effects, protein pharmaceuticals and other therapeutic compounds are combined to form nanoparticle conjugates. Such a conjugation facilitates targeted delivery of the medicine to the cells, tissues, and organs where it is needed. Numerous nanoparticles are available, depending on how and where a targeted protein needs to be administered to humans. The administration and efficacy of therapeutic proteins could be enhanced by the use of nanoparticles as the protein delivery method. Nanoparticles can cross biological barriers like the blood–brain barrier and perform cellular functions as a result of their small size. Through accumulating in target tissues, nanoparticles enhance the efficiency and effectiveness of medications, lowering the required dose and minimizing adverse effects. Although protein therapies have also demonstrated remarkable potential for nanotechnology-based techniques, the clinical development of protein delivery systems using nanoparticles is still in its early phases, and there are still a number of obstacles to overcome. To retain the protein cargo characteristics and prevent batch-to-batch variability, drug encapsulation must first be carefully managed.

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Chapter 2

Vaccines and sera

Garima Sahu, Priyanka Kumari and Amit K. Goyal,    Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Ajmer, Rajasthan, India

Abstract

Vaccines and serum therapy have led to a significant decrease and control of infectious diseases, but effective immunization remains elusive. Traditional and cutting-edge methods, as well as various platforms, for producing vaccines, have been used. The urgent need for vaccination has been brought home once more by the recent global spread of highly contagious diseases like Ebola, MERS, and SARS-CoV-2. Due to the complexity of the immunology of infectious diseases and a lack of knowledge, therapeutic vaccines for certain diseases are not yet available. However, next-generation platforms like DNA-derived vaccines, messenger RNA, virus-like particles, and recombinant technology offer an exciting and promising way to make vaccines, as they are cheap, safe, and effective and can be used by a large number of people quickly. These platforms, in contrast to conventionally derived vaccines, are likely to provide effective solutions for some infectious but noncurable disease like human immunodeficiency virus and noninfectious diseases like cancer. To combat the existing and emerging public health threats, increased funding and careful monitoring of new data are needed.

Keywords

Vaccines; sera; mRNA vaccines; DNA vaccines; recombinant vector; immunization; licensed vaccines; cancer vaccine; malarial vaccine; HIV vaccine; dengue