Handbook of Materials for Nanomedicine

Polymeric Nanomaterials

Vladimir Torchilin

• Publisher: Jenny Stanford Publishing
• Year: 2020
• ISBN:
  9781000067071
• Edition: 1
• Topic: Technology & Engineering
• Subtopic: Biomedical Science
• Index: Technology & Engineering

In the fast-developing field of nanomedicine, a broad variety of materials have been used for the development of advanced delivery systems for drugs, genes, and diagnostic agents. With the recent breakthroughs in the field, we are witnessing a new age of disease management, which is governed by precise regulation of dosage and delivery.

This book presents the advances in the use of polymeric nanomaterials for medical imaging, diagnosis, theranostics, and drug delivery. Beginning with the combinatorial approach for polymer design, it discusses star-shaped amphiphilic polymers, self-assembling polymer–drug conjugates, amphiphilic dendrimers, dendrimer nanohybrids, sustainable green polymeric nanoconstructs, chitosan-based nanogels, and multifunctional hybrid nanogels. The book provides all available information about these materials and describes in detail their advantages and disadvantages and the areas where they could be utilized successfully.

Chapter 1

Combinatorial Approach to Polymer Design for Nanomedicines

Amit Singh,^a Meghana Rawal,^a and Mansoor M. Amiji^b

^aAllExcel Inc., 135 Wood St., West Haven, Connecticut 06516, USA

^bDepartment of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts 02115, USA

[email protected]

1.1 Introduction

Recent developments in nanomaterial design and engineering have revolutionized the pharmaceutical and biomedical landscape in a major way. An increased interest in novel materials for such application has been driven by improved understanding in the material-biology interaction, better knowledge of cellular and sub-cellular level targets and advancement in our ability to study and characterize materials not only at the bench but also at the bedside. However, the evolution of nanoparticle-based therapeutics gained significant momentum due to multiple advantages it has to offer over traditional approach to drug development.

1.1.1 Advantages of Nanoparticle Drug Delivery Approach

A nanoparticle is a complex three-dimensional (3D) construct that could be designed to have multiple components with specific functions. Such complex constructs have been studied for several applications and have particularly revolutionized the way drug discovery is perceived today. A nanodrug delivery system can be engineered to offer following advantages: (1) improved half-life, pharmacokinetic (PK) and pharmacodynamic (PD) profile of a drug without a need to alter the drug molecule itself, (2) ability to target specific cells or tissues in the body to improve drug efficacy, mitigate adverse off-target effects and potentially lower the required dose for desired effect, (3) ability to deliver different type of drug molecules independently or in combination to aim at multiple disease targets simultaneously, (4) ability to target specific subcellular organelles, (5) ability to overcome biological barriers to deliver drug to difficult sites in the body, and (6) ability to combine imaging, diagnostic and therapeutic together. A nanoparticle drug formulation is an independent drug product comprising the active pharmaceutical ingredient (API), the drug delivery system (which may or may not have pharmaceutical value) and excipients. Therefore, from drug development and commercialization perspective, a nanoparticle drug formulation can be protected by intellectual property rights separately from the original API.

Discovery of the “stealth” property imparted by polyethylene glycol (PEG) modification of the nanoparticles was one of the most revolutionary development that provided impetus and cemented the faith that nanoparticle research could change the central dogma of drug development [1]. PEG decoration of nanoparticle surface aids in their prolonged systemic circulation by evading mononuclear phagocytic system (MPS) and activation of the complement system. Due to the tremendous impact of improved circulation half-life on the beneficial pharmacological properties of the drug product, multiple other strategies have also been adopted to diversify the repertoire of the “stealth” property imparting molecules [2]. The prolonged half-life of the nanoparticles in circulation assists in their accumulation in cancer tumors by a phenomenon called as “enhanced permeability and retention effect (EPR),” more often described also as “passive targeting” of nanoparticles [3]. Passive targeting by EPR effect, however, is limited to tumorous tissues that have leaky vasculature and poorly developed or completely dysfunctional lymphatic system [4]. Targeted drug delivery on the other hand aims at controlling the spatial distribution of the nanoparticle in the body by intentional use of affinity ligands specific to a cell or tissue. This approach is referred to as “active targeting” and is achieved by the use of specific ligands such as antibodies, peptides, sugars, or aptamer, among others [5].

1.1.2 Conventional Approach to Polymeric Drug Delivery

Polymers have been the most widely studied materials for drug delivery because of their rich history of applications in biomedical field, including implants, sutures, and medical devices and recently as drug carrier micro and nanoparticles [6]. The traditional approach to polymeric drug delivery system included use of biocompatible and biodegradable polymers that were used as drug-conjugates or carriers housing the API and ferrying them to the disease sites. The first generation of approved polymer drug delivery systems such as DOXIL™ lacked specific tissue targeting and controlled release; their use was intended at improving the drug half-life, safety, and efficacy. Since then, the efforts have significantly increased towards developing targeted polymeric delivery systems with more control over the PK/PD profile, drug release rates and better safety profile. This increased focus has led to a growing list of approved drug products and drug candidates in clinical trials but the rate of success is significantly low with extremely high attrition rate [7]. The major reason behind the poor success rate is the inherent challenge in engineering and manufacturing of the drug delivery constructs, which will be elaborated in a later section.

The conventional approach to development of a polymeric drug delivery system has been iterative and starts with selection of material looking at properties such as biocompatibility, biodegradability, immunogenicity/toxicity profile, interaction with intended API and so on. The selected polymeric backbone is then functionalized with various components following a series of reactions, to impart properties such as targeting, controlled drug release or ability to evade immune recognition. After binding/encapsulation of the API, the physicochemical properties such as size, charge, drug loading, drug protection and release or targeting ligand density are studied in vitro/in vivo. Depending on the outcome of the results, the drug delivery platform is either moved to the next stage of testing or discarded due to lack of desired outcome. Such a serial and iterative approach to synthesis of the desired final drug delivery platform is highly cumbersome, time- and labor-intensive, unreliable, inconsistent and prone to failure. Besides, tailorability and tunability of properties of the delivery platform is of utmost importance to have flexibility in choice of API(s), targeting ligand(s), imaging or diagnostic agent(s) or drug release rate. The lack of flexibility with the conventional approach has recently led to a shift in the overall outlook, where the need for a more rationalized approach has been acknowledged.

1.1.3 Combinatorial Design

Conceptually, nanoparticles should be envisioned as a 3D construct of multiple “building blocks,” each having a key role in the architecture and imparting a desired property to the final drug product. Building such a complex architecture with controlled properties requires precision in design and engineering. Therefore, recent efforts in discovery of polymeric drug delivery systems have relied on a more customizable and modular platform technology using combinatorial design. The concept of combinatorial design is not new and has been extensively utilized in drug discovery through high-throughput screening. This approach utilizes computational methods to generate a library of compounds that are then synthesized and mapped by systematic analysis of experimental data to identify positive “hits.” The same principle has been extended to material discovery where a suitable polymer backbone is modified with different chemical entities to generate a library of derivatives with a varying range of physicochemical properties. These derivatives can be screened based on the prior knowledge of drug candidate for target disease to study the structure–property relationship and choose the optimal combination of derivatives to devise the suitable drug delivery system.

1.1.3.1 Parallel synthesis of “building blocks”

The core concept behind combinatorial design of material focuses on parallel synthesis of polymer derivatives without any predisposition on their end application. Unlike the conventional approach where the polymer is derived with multiple functionalities by a series of reaction and purification steps in between, combinatorial approach intends on development of various derivatives on the polymer backbone independently [8]. Each derivative serves as a “building block” and exhibits a certain property or character that can be used if that property is desirable in the final architecture. Appropriate analogy for such approach would be “Lego™ blocks,” where certain permutation and combination of the blocks are applied to obtain a structure and the composition of the blocks differs from structure to structure. On a similar note, a library of polymer derivatives can be synthesized, characterized, and their properties defined prior to their use in certain combination. Since this approach is independent of the payload properties, there is no limit to the type or number of derivatives that can be synthesized to build a library. This provides an enormous pool of polymer which are derived from the same backbone but have different distinct properties. Polymers are ideal candidate for such synthetic approach because they have abundance of similar functional groups in monomeric repeats and thus provide an avenue to develop robust synthetic process. Alternatively, in certain cases it may be desirable to have two or more polymers in the same nanoparticle and can be easily achieved without the need for a complex synthetic method.

1.1.3.2 Controlling property by “mixing and matching”

The library of the polymer derivatives can be utilized by “mixing and matching” to design a series of polymeric ensemble nanoparticles that are screened for drug loading capability, release profile, targeting capability and other selection parameters (Fig. 1.1) [9]. The nanoparticles that show “positive hits” could be taken for more rigorous selection criteria like in vitro/in vivo safety and efficacy to triage nonperformers and select the best performing drug candidate. This approach provides flexibility in tuning the property of the nanoparticle such as hydrophlicity/hydrophobicity ratio, extent of surface charge, density of PEG, imaging or diagnostic agent or target ligand on the surface, etc. For example, if the API of choice has a highly hydrophobic nature and requires a hydrophobic core for encapsulation, a nanoparticle designed with long carbon-chain lipid derivative will theoretically be a preferred choice than that with a smaller chain lipid modification. However, it would be impossible to theoretically predict the optimum chain length of lipid that would lead to the ideal selection parameter for the final drug delivery system. Screening a library of polymer which comprises derivatives of different lipid chain length against desired properties such as drug loading or size and surface charge of the nanoparticle can help in identifying the “magical spot” for that drug candidate. Similarly, during the process of nanoparticle formation, the building block with drug encapsulation property can be blended in different ratios with the block for targeting or imaging or diagnostics and so on to select the perfect ratio based on the selection criteria.

Figure 1.1 Schematic describing the high-throughput “mix and match” methodology for screening multifunctional polymeric nanosystems for drug delivery. Reprinted with permission from [9]. Copyright (2018) American Chemical Society.

1.1.3.3 Advantages to Combinatorial Design

The modern day medicine does not rely on a single drug; most often a combination of drugs is used to obtain maximum therapeutic benefit against a disease. Sometimes, gene and small molecule drug combination is a preferred therapy. Combinatorial design offers flexibility to use the same platform technology for delivery of payloads with extremely different nature. It provides a customizable and modular platform where the properties of the delivery system can be tailored to accommodate a variety of drug candidates (small molecules, nucleic acids, proteins, and peptides), imaging or diagnostic agents, targeting ligands, or any other desired component. The use of a modular design and, therefore, helps in achieving several properties desirable in an ideal delivery system, including: (1) a biocompatible and biodegradable core polymeric precursor, (2) freedom of using one or more targeting ligand in a single construct, (3) ease of including one or more types of drugs in a delivery system with same polymer backbone, (4) ease at modulating the physicochemical properties of the nanoparticle, (5) ability to use imaging and diagnostic agents without compromising the...

Table of contents

• Cover
• Half Title
• Series Page
• Title Page
• Copyright Page
• Table of Contents
• 1. Combinatorial Approach to Polymer Design for Nanomedicines
• 2. Star-Shaped Amphiphilic Polymers as Soluble Carriers for Drug Delivery
• 3. Self-Assembling Polymer–Drug Conjugates Nanomedicine for Drug Delivery
• 4. Amphiphilic Dendrimers for Drug Delivery
• 5. Dendrimer Nanohybrids for Drug Delivery
• 6. Physico-Chemical Bases of the Fabrication of Platforms for Encapsulating Active Compounds Using the Layer-by-Layer Method
• 7. Sustainable Green Polymeric Nanoconstructs for Active and Passive Cancer Therapeutics
• 8. Chitosan-Based Nanogels for Biomedical Applications
• 9. Multifunctional Hybrid Nanogels for Medicine
• 10. Nanogels in Medicine
• Index