POLYMERIC DRUG DELIVERY TECHNIQUES Translating Polymer Science for Drug Delivery aldrich.com/matsci Solubility Enhancement Preface Low drug solubility and stability often reduce the effectiveness of an Rapid advances in medicine and otherwise promising therapeutic candidate. Drug delivery systems biotechnology have driven the field of drug can be formulated to improve the in vivo solubility of lipophilic and discovery and led to the development of hydrophobic drugs by encapsulation in a drug delivery carrier or by many new highly potent and target-specific conjugation with a polymer. drug candidates. Despite the fast pace of research and early-stage discovery, many drug candidates fail during preclinical evaluation Selecting a Polymeric Drug Delivery System due to poor efficacy, limited bioavailability, There are three main categories of polymeric drug delivery systems; and other challenges associated with effective Nicolynn Davis, Ph.D. colloidal carriers (micro, nanoparticles, micelles, micro/nanogels), drug delivery. Small molecule drugs can Aldrich Materials Science implantable networks or hydrogels, and polymer drug conjugates. suffer from low solubility, poor stability, short Sigma-Aldrich, Milwaukee, WI USA Email: [email protected] Unfortunately, there is no “silver bullet” for effective delivery of circulation time, and non-specific toxicity broad classes of therapeutics. Rather, selection of a drug delivery limiting their therapeutic efficacy. Biopharmaceuticals such as nucleic system must be driven by the nature of the drug and the inherent acids, peptides, and proteins are often limited by poor stability and properties of the drug delivery system (Figure 1). Drug properties, rapid clearance from the body. These challenges, coupled with the including chemistry, solubility, potency, site of action, and clearance complexity and diversity of new pharmaceuticals, are fueling the rate, each impact the proper selection of a drug delivery system that evolution of novel drug delivery systems that overcome bioavailability can achieve the desired outcomes. In addition, the choice of drug and delivery obstacles. However, despite the growing importance of delivery system determines the drug loading capacity, longevity of polymer drug delivery methodologies, the materials and methods of release, and the route best suited for administration. Furthermore, drug delivery are not widely available to those outside the polymer characteristics of the drug delivery system (size, surface charge and synthesis field. hydrophobicity, shape, flexibility, inclusion of targeting moieties) will The objective of effective drug delivery is improving the affect performance and distribution in the body. Each drug delivery pharmacokinetics and pharmacodynamics of each therapeutic to system has inherent advantages and limitations (Table 1). It should be enable drug delivery to the right place, at the right time and in the noted that drug release from any carrier is determined by a complex right amount. Delivery systems apply three main strategies to enable interaction between the drug properties, polymer characteristics, and improved drug efficacy. environmental/in vivo conditions. Controlled Release Drug Drug efficacy can be enhanced by maintaining the concentration • Drug properties within the therapeutic window (effective dose). Polymer carriers loaded (solubility, stability) with therapeutics enable controlled temporal and spatial release • Desired site of Drug Delivery System Formulation action • Loading capacity of a drug by controlling drug diffusion, the rate of dissolution, or • Desired release rate • Route of degradation of the carrier. • Delivery challenge administration Polymer Selection associated with drug • Compatibility with Targeted Delivery drug Drug efficacy can be enhanced and toxicity minimized by localization • Desired release kinetics, including at the organ, tissue, cellular, or organelle level. Targeting can be degradation rate achieved by coating or conjugating the carrier with affinity reagents such as nucleic acids, peptides, antibodies, or others that bind specific cell receptor proteins, nucleic acids, or polysaccharides. Figure 1. Drug delivery formulation selection process. Table 1. Advantages and limitations of drug delivery systems. Drug Delivery System and Polymer Types Advantages Limitations Microparticles • Biodegradable polymers • Encapsulate a variety of drugs • Burst release possible, may lead to local toxicity • Natural polymers • Sustained release can be achieved Nanoparticles • Biodegradable polymers • Stable delivery system • Non-specific uptake in RES • Natural polymers • Small size enables enhanced retention and permeation into tissue and tumor Micelles • Amphiphilic block copolymers • Enhanced solubility for hydrophobic drugs • Less stable, may require additional crosslinking • Facile synthesis Drug Conjugates • Hydrophilic polymers • Extended circulation half-life, reduced clearance due to increased drug • Activity of drug can decrease due to conjugation • Dendrimers hydrodynamic radius • Approach provides sustained but not controlled release • Decreased drug immunogenicity and degradation • Low loading capacity of drug Hydrogels or Implants • Hydrophilic polymers • Broad range of release timeframes (weeks to months) • Drug solubility may limit utility • Biodegradable polymers • Useful for localized delivery • Limitation to route of delivery achievable • Natural polymers • Improved patient compliance due to infrequent dosing • Delivery may require incision or larger gauge needle • Risk of local dose dumping TO ORDER: Contact your local Sigma-Aldrich office or visit aldrich.com/matsci. Drug Delivery Material Choices Table of Contents Polymer selection greatly influences the performance of the drug delivery system. Careful polymer selection is essential to control the Articles encapsulation efficiency, release rate, and duration of release. Many polymers can be formulated into various drug delivery systems to Colloidal Carriers for Drug Delivery address the three key drug delivery strategies to enable improved Polymer Micelles for Drug Delivery 3 drug efficacy (Table 2). The diversity of polymer building blocks Alice Du, Martina Stenzel can further complicate formulation decisions. As discussed by Du and Stenzel (in this publication), the most critical factor in polymer Biodegradable Colloidal Carriers in Drug Delivery Applications 8 selection is considering the interaction of the drug and polymer. Bin Wu, Theresa Logan Polymer selection will determine the mechanism for drug release (bulk Lipid-polymer Hybrid Nanoparticles for Drug Delivery Applications 14 erosion, system degradation), and the choice of polymer properties Sangeetha Krishnamurthy, Juliana M. Chan (molecular weight, surface charge) will influence release rate and impact pharmacokinetics. Further fine-tuning of release from drug Crosslinked Chitosan Nanoparticles and Chemical Modifications for 18 delivery systems can be achieved by using multiple types of polymers Drug Delivery Applications or including additives. Shady Farah, Joshua Doloff, Daniel Anderson, Robert Langer Table 2. Polymer categories and the drug delivery strategies they enable. Poly(N-isopropylacrylamide)-based Stimuli-responsive Materials 22 Ganga Panambur, Nicolynn Davis Controlled Targeted Solubility Shape Change Poly(N-isopropylacrylamide) Microstructures 28 Release Delivery Enhancement for Drug Delivery Tanvi Shroff, ChangKyu Yoon, David H. Gracias Biodegradable nanoparticles ✔ ✔ Biodegradable micelles ✔ Hydrogels for Drug Delivery Responsive polymers ✔ ✔ Formulation of Poly(ethylene glycol) Hydrogels for Drug Delivery 31 Polymeric hydrogels ✔ ✔ Tyler Lieberthal, W. John Kao PEG conjugation ✔ Drug Conjugates Polyoxazoline polymers ✔ Dendrimers ✔ ✔ Protein PEGylation 36 Steve Brocchini Poly(2-oxazoline)s for Drug Delivery 42 About This Guide Rainer Jordan, Robert Luxenhofer, Alexander V. Kabanov This guide is intended to provide an overview of polymeric drug Polyoxazolines: An Alternative to Polyethylene Glycol 46 delivery systems as well as provide the corresponding example Nicolynn Davis formulation protocols and product information required to utilize these techniques in the laboratory. The publication has been developed Dendritic Polyester Scaffolds: Functional and Biocompatible Precision 47 to enable those without a polymer chemistry background to use Polymers for Drug Delivery Applications polymers to solve their drug delivery research challenges; but, we have Sandra García-Gallego, Michael Malkoch also kept the expert in mind by including a number of cutting-edge RAFT Polymeric Carriers for Antibody Drug Conjugates of Biologic Drugs 52 methodologies. This guide is arranged according to drug delivery Patrick S. Stayton, Anthony Convertine, Geoffrey Berguig strategies, and these strategies are noted within each method. We hope this publication will enable chemists, engineers, pharmaceutical Linear and Branched PEIs as Nonviral Vectors for Gene Delivery 57 scientists, and biologists to explore different drug delivery techniques Philip Dimitrov, Nicolynn Davis to facilitate translational research. Featured Products Diblock Copolymers 6 Poly(lactide-co-glycolide) Copolymers 11 End-functionalized Poly(L-lactide)s 12 PNIPAM and End-functionalized PNIPAM 26 Bifunctional and Multi-arm PEGs 33 Poly(oxazoline)s 45 bis-MPA Dendrimers and Hyperbranched PEG Dendrimers 50 Indexes Method 60 Trademark 60 For questions, product data, or new product suggestions, contact