Journal of Controlled Release 161 (2012) 446–460
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Journal of Controlled Release 161 (2012) 446–460 Contents lists available at SciVerse ScienceDirect Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel Review Administration, distribution, metabolism and elimination of polymer therapeutics Ela Markovsky, Hemda Baabur-Cohen, Anat Eldar-Boock, Liora Omer, Galia Tiram, Shiran Ferber, Paula Ofek, Dina Polyak, Anna Scomparin, Ronit Satchi-Fainaro ⁎ Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel article info abstract Article history: Polymer conjugation is an efficient approach to improve the delivery of drugs and biological agents, both by Received 6 September 2011 protecting the body from the drug (by improving biodistribution and reducing toxicity) and by protecting the Accepted 16 December 2011 drug from the body (by preventing degradation and enhancing cellular uptake). This review discusses the Available online 29 December 2011 journey that polymer therapeutics make through the body, following the ADME (absorption, distribution, metabolism, excretion) concept. The biological factors and delivery system parameters that influence each Keywords: stage of the process will be described, with examples illustrating the different solutions to the challenges Polymer therapeutics Angiogenesis of drug delivery systems in vivo. ADME © 2011 Elsevier B.V. All rights reserved. Biodistribution Angiogenesis-dependent diseases Cancer Contents 1. Introduction .............................................................. 446 1.1. Administration.......................................................... 447 1.2. Distribution ........................................................... 449 1.2.1. Travelling to the site of action .............................................. 449 1.2.2. Disease site microenvironment .............................................. 452 1.2.3. Cell internalization ................................................... 453 1.3. Metabolism and degradation ................................................... 455 1.3.1. Biodegradable polymers ................................................. 455 1.3.2. Semi-degradable polymer backbones ........................................... 455 1.4. Elimination of non-degradable polymers.............................................. 456 2. Summary ............................................................... 456 Acknowledgments .............................................................. 456 References ................................................................. 457 1. Introduction attached a drug to the water-soluble polymer polyvinylpyrrolidone (PVP) in the 1950s [1,2] and Ushakov and his group synthesized more Many therapeutic agents are low-molecular weight compounds water soluble conjugates during the following years [2-4]. which are administered systemically and exhibit non-specific biodistri- An excellent analysis of a complete polymer-bound drug delivery bution profile, short plasma circulation time and rapid systemic elimi- system was first proposed by Helmut Ringsdorf in 1975 [5]. This pro- nation. Consequently, relatively small amounts of the drug reach the posed model consists mainly of five components: (i) macromolecular target site, and therapy is associated with side effects and low efficacy. polymeric backbone, (ii) drug, (iii) spacer, (iv) targeting moiety and The use of macromolecules as carriers was suggested over 50 years (v) solubilizing agent. Macromolecular carriers chosen for the prepa- ago, mainly in order to avoid or improve those downsides. Jatzkewitz ration of polymer therapeutics should ideally be water-soluble, non- toxic, non-immunogenic, and also biodegradable and/or being able ⁎ Corresponding author. Tel.: +972 3 640 7427; fax: +972 3 640 9113. to eliminate from the organism [6,7]. Finally, the macromolecular car- E-mail address: [email protected] (R. Satchi-Fainaro). rier should exhibit suitable functional groups for attaching the 0168-3659/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2011.12.021 E. Markovsky et al. / Journal of Controlled Release 161 (2012) 446–460 447 respective drug or spacer. The drug can be conjugated directly or via a 1.1. Administration degradable or non-degradable linker onto the polymer backbone to allow the release of the active drug from the conjugate at the target The vast majority of polymer therapeutics that are being devel- site [8]. oped are designed to be administered by injection, usually intrave- The choice of polymeric backbone for the conjugate has great im- nous (IV). The IV administration is the most straightforward plications on the pharmacokinetics and pharmacodynamics of the method and its advantages are obvious, as it enters the bloodstream drug. The polymer characteristics, such as molecular weight, polydis- directly and is distributed throughout the body within seconds. persity, architecture, charge and hydrophilicity, define the drug Several formulations in the market today are designed to be admin- solubility and loading, its biodistribution, body excretion and the in- istered subcutaneously (SC) and intramuscularly (IM) (Peg-intron®, teraction with the immune system. The polymeric backbone of Pegasys®, Adagen® and more). These routes of administration allow the conjugate can be biodegradable, non-biodegradable, or semi- for slow release of the drug from the injection site to the bloodstream, biodegradable. and therefore less frequent injections are required. For a suitable conjugation to chemical and biopharmaceutical drugs, Following evaluation of the biological fate of PVA and PEG of var- many polymers have been proposed as carriers, including N-(2-hydroxy- ious molecular weights injected via different routes (intraperitoneal propyl)methacrylamide (HPMA) copolymers, poly(ethyleneimine) (PEI), (IP), SC, and IM), Yamaoka et al. found the elimination rate to be linear polyamidoamines, polyvinylpyrrolidone (PVP), polyglutamic acid IP>SC>IM, with lower molecular weight polymers eliminated soon- (PGA), polyacrylamide (PAM), polydimethylacrylamide (PDMA), polyvi- er, for both polymer types [10]. nyl alcohol (PVA), chitosan and dextran. It is important to note that poly- The injection administration methods hold many drawbacks for ethylene glycol (PEG) has significant contribution specifically in the field the patient and therefore lead to poor patient compliance. When de- of polymer–protein conjugates. PEGylation has been proven to be one of signing a treatment intended for long-term therapy, a more conve- the most straightforward procedures for enhancing the therapeutic and nient administration method should be considered. biotechnological potential of peptides and proteins [8].Themostcom- Oral administration is the best route in terms of patient compliance. mon types of polymeric carriers used in the field of polymer therapeutics However, an orally-administered drug needs to pass several barriers on are presented in Fig. 1 and the most common polymer backbones are pre- its way to systemic circulation, such as acidic environment in the stom- sented in Fig. 2. ach, proteases in the gut lumen and brush border membrane (BBM), Many reviews had been published discussing different aspects of tightly-bound intestinal epithelial cells (enterocytes) and metabolism the growing field of polymer therapeutics. The descriptor ‘polymer by liver enzymes (the “first-pass effect”). All these factors may consid- therapeutics’, defined by R. Duncan, is an umbrella term used to de- erably decrease the bioavailability of the drug. Nevertheless, several scribe polymeric drugs, polymer–drug conjugates, polymer–protein successful oral formulations of polymer–drug conjugates have been de- conjugates, polymeric micelles to which drug is covalently bound, veloped. In the field of oral drug delivery, conjugation to polymers can and multicomponent polyplexes that are being developed as non- be used to: 1) protect sensitive drugs from degradation in stomach viral vectors [9]. In this review, we will focus on the journey that and gut lumen [11]; 2) enhance absorption in the intestine by increas- polymer therapeutics make through the body, following the ADME ing water solubility [12,13]; 3) overcome drug resistance mechanisms (absorption, distribution, metabolism, excretion) concept (Fig. 3). (MDR) by altering the absorption pathway from transcellular to para- We will start by discussing the different methods of administration; cellular or transcytosis routes [12-14] (topic of drug resistance is continue with the factors that govern the biodistribution of these con- addressed in detail below); 4) protect the drug from first pass effect jugates, their internalization to the target organs, their degradation degradation by liver enzymes [11-14]. and the release of free drug within the target cells. Finally, we will NKTR-118 is an orally-administered formulation of the anti-opiate present the issue of polymers' metabolism and their ways of elimina- naloxone conjugated to PEG, currently in Phase III clinical trial [15]. tion. We will describe the biological factors and delivery system pa- PEGylation of naloxone alters its pharmacokinetic properties, distri- rameters that influence each stage of the process, and present bution, and metabolism. It reduces the first-pass effect, increases its examples illustrating the different solutions to the challenges of bioavailability and limits its capacity to enter the CNS, while the opi- drug delivery systems in vivo. It is