Biomaterials for Delivery and Targeting of Proteins and Nucleic Acids

Ram I. Mahato

• Publisher: CRC Press
• Year: 2004
• Print ISBN:
  9780849323348
• eBook ISBN:
  9781135487843
• Topic: Technology & Engineering
• Subtopic: Pharmacology
• Index: Technology & Engineering

Newcomers to the field of biopharmaceuticals require an understanding of the basic principles and underlying methodology involved in developing protein- and nucleic acid-based therapies for genetic and acquired diseases. Introducing the principles of polymer science and chemistry, this book delineates the basic biology required for understanding how biomaterials can be used as drug-deliver vehicles. No book to date combines a discussion of high-tech biomaterials-based delivery of protein and nucleic acid drugs with the pharmaceutical or biocompatibility aspects. Leading experts from around the world discuss the physiochemical parameters used for design, development, and evaluation of biotechnological dosage forms for delivery of proteins, peptides, oligonucleotides, and genes. The book includes coverage biological barriers to extravasation and cellular uptake of proteins and nucleic acids.

1
Structure, Properties, and Characterization of Polymeric Biomaterials
Anjan Nan and Hamidreza Ghandehari

1.1 INTRODUCTION

Biomaterials is a term used to indicate materials that constitute the basic framework of medical implants, extracorporeal devices and disposables utilized in medicine, surgery, dentistry, veterinary, as well as in other aspects of medical care. Biomaterials can be natural or synthetic in origin. They are used in a variety of ways from being carrier molecules for delivery of bioactive agents (small molecular weight drugs, proteins, peptides, oligonucleotides, and genes) or as whole or part of systems that augment or replace tissues or organs. The term “biomaterials” make them unique from other classes of materials in that they are required to meet special biocompatibility criteria (as discussed in Chapter 6) for acceptance in the biological system. Polymeric constructs are a major component of biomaterials.

Polymers are macromolecules consisting of multiple repeating units or monomer residues linked together usually by covalent linkages. End-groups are the structural units that terminate polymer chains. Polymers containing reactive end-groups to allow for further chemical modification are called telechelic polymers. The monomers in polymeric systems can be linked together in various ways to give rise to linear chains, branched or three-dimensional cross-linked networks (Figure 1.1). A linear polymer has no branching. A typical example is poly(ethylene glycol) (PEG) (Table 1.1). Linear polymers can have pendent groups associated with them. Example of linear polymeric systems with pendent side-groups are N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers (Table 1.1). Branched polymers are those in which the molecules have been formed by branching as opposed to a linear polymer. A polymer with a high degree of three-dimensional tree-like branching starting from a core is called a dendrimer. Three-dimensional polymers are also formed by physical or chemical cross-linking of polymer strands to form a network. A typical example of such a structure is a hydrogel. Hydrogels are three-dimensional polymeric networks that swell in water but do not dissolve.

Polymers can be classified based on the general composition of the monomeric components as homochain polymers and heterochain polymers. In homochain polymers the polymer chain or backbone consists of a single type of atom. Primarily this is carbon with other atoms or groups of atoms attached. Heterochain polymers such as polyethers or polyesters contain more than one atom type in the backbone. The degree of polymerization refers to the total number of structural monomeric units including end groups and is thus related to the chain length and the molecular weight.

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FIGURE 1.1 Various types of polymeric architectures: (a) linear with end-chain; (b) linear with side-chain; (c) branched; (d) cross-linked and (e) dendritic. Drugs can be attached to or dispersed in these polymers.

TABLE 1.1
General and specific structures of some commonly used polymers in drug delivery

FIGURE 1.2 Various types of copolymers based on monomeric arrangements: (a) random; (b) alternating; (c) block and (d) graft. These structures comprise of A and B as two representative comonomers. Polymers can also be synthesized to contain more than two types of comonomers.

Another way to classify polymers is based on the constituents of the chain. A polymer prepared from a single monomer is called a homopolymer. If two or more types of monomers are employed it is called a copolymer. Depending on the arrangement of monomers, various types of copolymers can be identified. The monomeric units may be randomly distributed (random copolymer), in alternating fashion (alternating copolymer), or in blocks (block copolymer). A graft copolymer consists of one polymer grafted to the backbone of the other. Using A and B to denote the two different monomers, various types of copolymers are depicted in Figure 1.2. Polymers are conventionally classified based on two major methods of synthesis namely chain polymerization and step-growth polymerization. Details of such classification and synthesis are discussed in the latter chapters of this book.

The following section provides the reader with a general overview of the different types of polymers that are used primarily in biomedical applications with an emphasis on drug delivery. For a more detailed classification and properties of polymers the readers are referred to the Encyclopedia of Polymer Science and Technology.¹ Table 1.1 lists the structures of commonly used polymers in drug delivery as discussed in the following sections. The list is not comprehensive and intends to introduce some of the polymers used in this field.

1.2 SYNTHETIC POLYMERS

1.2.1 BIODEGRADABLE POLYMERS

Biodegradable polymers break down to smaller fragments due to pH change or enzymatic hydrolysis. The following section reviews the characteristics of some commonly used families of biodegradable polymers used in medicine and drug delivery.

1.2.1.1 Poly(ortho ester)s

Poly(ortho ester)s were pioneered for biomedical applications in the 1970s by Choi and Heller at Alza Corporation (Palo Alto, CA) under the name of Alzamer®. These polymers have been categorized into three major families, namely I, II, and III, based on their methods of synthesis and polymer degradation mechanisms.² These polymers usually undergo hydrolysis in an aqueous environment to produce a diol and a lactone, which rapidly converts to ã-hydroxybutyric acid. The ã-hydroxybutyric acid autocatalyzes the hydrolysis reaction. The rate and extent of degradation by autocatalysis can be controlled by incorporation of a basic moiety such as sodium bicarbonate. Poly(ortho ester)s have been used for a number of drug delivery applications.³ For example poly(ortho ester) I has been used for delivery of the narcotic antagonist Naltrexone,⁴ while poly(ortho ester) III has been used for delivery of 5-fluorouracil as an adjunct for glaucoma filtration surgery. Several modifications of poly(ortho ester)s have been introduced over the years, which allow synthesis under milder conditions, or polymers, which are ointment at room temperature rendering them suitable for topical and periodontal applications.⁵

1.2.1.2 Poly(phosphoester)s

This family of polymers is comprised of the polyphosphates, polyphosphonates, and polyphosphites, which are synthesized by altering the functional group on the main chain (R) or the side chain (RŒ) of the general polymer backbone (Table 1.1). Accordingly the physicochemical properties of these polymers can be changed. Also by modifying the backbone of these polymers, controlled biodegradation can be achieved. These polymers can be synthesized with high molecular weights of over 100,000 resulting in good mechanical properties. The hydrolytic breakdown products of these polymers are phosphates, alcohols, and diols which are all potentially nontoxic. The pentavalent phosphorus atom easily allows chemical conjugation of drugs and other molecules to the polymer side chain. Several examples of poly(phosphoester) (PPE)-based drug delivery systems are reported in the literature. PPE microspheres have been used to deliver drugs such as paclitaxel, cisplatin, and lidocaine.⁶ The rate of drug release has been shown to depend on the side chain length of the polymer. Recently PPE-based microspheres were used in the controlled release of plasmid DNA with an encapsulation efficiency as high as 88–95%.⁶

1.2.1.3 Polyanhydrides

The anhydride linkage in polymer chains is highly susceptible to hydrolysis. As a result several properties are required for preparing stable anhydride devices. Of particular interest in drug delivery are polymers where hydrolysis results in surface erosion. For example, the anhydride copolymer of sebacic acid and carboxyphenoxypropane resists water penetration due to the hydrophobic carboxyphenoxypropane residue, yet degrades into low molecular weight fractions at the water/polymer interface owing to the presence of anhydride bond. By appropriately selecting the copolymerization ratios we can modulate the hydrophobicit...

Table of contents

• COVER PAGE
• TITLE PAGE
• COPYRIGHT PAGE
• DEDICATION
• PREFACE
• ABOUT THE EDITOR
• CONTRIBUTORS
• 1: STRUCTURE, PROPERTIES, AND CHARACTERIZATION OF POLYMERIC BIOMATERIALS
• 2: STEP-GROWTH AND RING-OPENING POLYMERIZATION
• 3: COPOLYMERS, BLOCK COPOLYMERS, AND STIMULI-SENSITIVE POLYMERS
• 4: POLYMER SOLUTION PROPERTIES, MICELLES, DENDRIMERS, AND HYDROGELS
• 5: PROTEIN CONJUGATION, CROSS-LINKING, AND PEGYLATION
• 6: COMPLEMENT ACTIVATION BY INJECTABLE COLLOIDAL DRUG CARRIERS
• 7: BIOLOGICAL MEMBRANES AND BARRIERS
• 8: PHARMACOKINETICS OF PROTEIN- AND NUCLEOTIDE- BASED DRUGS
• 9: IN VIVO FATE OF POLYMERIC GENE CARRIERS
• 10: SUBCELLULAR FATE OF PROTEINS AND NUCLEIC ACIDS
• 11: STABILITY OF PROTEINS AND NUCLEIC ACIDS
• 12: FORMULATION, STABILITY, AND CHARACTERIZATION OF PROTEIN AND PEPTIDE DRUGS
• 13: MICRO- AND NANOPARTICULATE POLYMERIC DELIVERY SYSTEMS FOR NUCLEIC ACID-BASED MEDICINE
• 14: LIPOSOMAL DELIVERY OF PROTEIN AND PEPTIDE DRUGS
• 15: MECHANISMS OF CELLULAR DRUG RESISTANCE AND STRATEGIES TO OVERCOME IT
• 16: TRANSPORTERS AS MOLECULAR TARGETS FOR DRUG DELIVERY AND DISPOSITION
• 17: PROTEIN TRANSDUCTION DOMAIN AS A NOVEL TOOL FOR DELIVERY OF PROTEINS, PEPTIDES AND NUCLEIC ACIDS
• 18: INTRODUCTION TO THERAPEUTIC NUCLEIC ACIDS
• 19: ANTISENSE AND ANTIGENE OLIGONUCLEOTIDES: STRUCTURE, STABILITY AND DELIVERY
• 20: ARTIFICIAL NUCLEIC ACID CHAPERONES
• 21: BASIC COMPONENTS OF PLASMID-BASED GENE EXPRESSION SYSTEMS
• 22: DESIGN ELEMENTS OF POLYMERIC GENE CARRIERS