Are Nanoparticles an Option for Treating Osteoporosis?
Total Page：16
File Type：pdf, Size：1020Kb
International Journal of Molecular Sciences Review Targeting Drug Delivery in the Elderly: Are Nanoparticles an Option for Treating Osteoporosis? Gudrun C. Thurner 1,* , Johannes Haybaeck 1,2 and Paul Debbage 3,* 1 Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Müllerstraße 44, 6020 Innsbruck, Austria; [email protected] 2 Diagnostic & Research Center for Molecular BioMedicine, Institute of Pathology, Medical University Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria 3 Department of Anatomy, Histology and Embryology, Medical University of Innsbruck, Müllerstraße 59, 6020 Innsbruck, Austria * Correspondence: [email protected] (G.C.T.); [email protected] (P.D.) Abstract: Nanoparticles bearing specific targeting groups can, in principle, accumulate exclusively at lesion sites bearing target molecules, and release therapeutic agents there. However, practical application of targeted nanoparticles in the living organism presents challenges. In particular, intravasally applied nanoparticles encounter physical and physiological barriers located in blood vessel walls, blocking passage from the blood into tissue compartments. Whereas small molecules can pass out of the blood, nanoparticles are too large and need to utilize physiological carriers enabling passage across endothelial walls. The issues associated with crossing blood-tissue barriers have limited the usefulness of nanoparticles in clinical applications. However, nanoparticles do not encounter blood-tissue barriers if their targets are directly accessible from the blood. This review focuses on osteoporosis, a disabling and common disease for which therapeutic strategies are limited. The target sites for therapeutic agents in osteoporosis are located in bone resorption pits, and these are Citation: Thurner, G.C.; Haybaeck, J.; Debbage, P. Targeting Drug Delivery in immediate contact with the blood. There are specific targetable biomarkers within bone resorption in the Elderly: Are Nanoparticles an pits. These present nanomedicine with the opportunity to treat a major disease by use of simple Option for Treating Osteoporosis? Int. nanoparticles loaded with any of several available effective therapeutics that, at present, cannot be J. Mol. Sci. 2021, 22, 8932. https:// used due to their associated side effects. doi.org/10.3390/ijms22168932 Keywords: osteoporosis; nanoparticles; tissue-barriers; Howship’s lacuna; targeting Academic Editors: Sang-Kyung Lee, Irfan Ullah and Qurrat Ul Ain Received: 30 July 2021 1. Nanoparticles as Drug-Delivery Agents Accepted: 16 August 2021 A nanoparticle (NP) is a nanomachine constructed according to certain principles Published: 19 August 2021 that are still in the process of development. The use of targeted nanoparticles to transport drugs into lesions is a leading goal of nanomedicine. The core idea is to package several Publisher’s Note: MDPI stays neutral hundred drug molecules into one single nanoparticle (Figure1), and to attach suitable with regard to jurisdictional claims in targeting groups to the nanoparticle’s surface in order to steer it into a defined lesion [1]. published maps and institutional affil- iations. The properties of the packaged drug molecules then no longer affect the bio-distribution, targeting and clearance of the drug. Instead, the properties engineered into the nanopar- ticle define a pre-programmed bio-distribution, with targeting and release of the drug (ideally exclusively) into the diseased site. Naturally evolved targeted nanoparticles, such as viruses, are of breathtaking complexity and show that the packaging/targeting principle Copyright: © 2021 by the authors. is capable of great sophistication [2] and delivers active agents efficiently. At present, Licensee MDPI, Basel, Switzerland. however, artificially prepared nanoparticles lack intrabatch homogeneity in size, interbatch This article is an open access article reproducibility, in vivo stability, long-term storage stability and upscalability to kilogram distributed under the terms and conditions of the Creative Commons amounts, preventing their clinical translation and industrial production [3–7]. This chal- Attribution (CC BY) license (https:// lenge of developing medically safe and effective nanoparticles is reflected in the rather creativecommons.org/licenses/by/ low number of nanoparticles that have already entered clinical use. To date, only about 4.0/). Int. J. Mol. Sci. 2021, 22, 8932. https://doi.org/10.3390/ijms22168932 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 20 Int. J. Mol. Sci. 2021, 22, 8932 2 of 21 about 50 nanoparticulate formulations have been approved by regulatory authorities 50[6,8]. nanoparticulate However, this formulations review of osteopo have beenrosis approved addresses by a regulatorydisease with authorities high social [6, 8and]. How- eco- ever,nomic this costs, review with of about osteoporosis 200 million addresses patients a diseaseworldwide, with and high causing social and significant economic morbid- costs, withity and about mortality 200 million in elderly patients people worldwide, [9], a disease and causing for which significant nanotechnology morbidity could and mortality offer the inpossibility elderly people of site- [directed9], a disease drug for delivery. which Several nanotechnology established could therapies offer theare possibilityavailable but of site-directedare accompanied drug delivery.by side effects Several that established are often severe therapies (see are Section available 8). Treatment but are accompanied using suit- byably side targeted effects nanoparticles that are often could severe reduce (see the Section frequently8). Treatment occurring using severe suitably side effects targeted that nanoparticlesaccompany current could reducetreatment the options frequently [10]. occurring However, severe no nanoparticle side effectsthat formulation accompany has cur- yet rentbeen treatment approved options for treatment [10]. However, of osteoporosis. no nanoparticle This mini formulation-review delineates has yet beensome approved possibili- forties treatment of developing of osteoporosis. nanoparticles This for mini-review clinical application delineates in some treating possibilities osteoporosis. of developing The main nanoparticlesfocus of this article for clinical, therefore application, lies in in the treating importance osteoporosis. of “targeting”. The main The focus review of this first article, dis- therefore,cusses the lies biological in the importance background of of “targeting”. successful targeting The review in the first context discusses of the the presence biological of backgroundtissue barriers, of successfulthen moves targeting on to discuss in the the context physiology of the of presence bone and of re tissuespective barriers, targets then for movesosteoporosis, on to discuss and closes the physiologywith a discussion of bone of and potential respective therapeutic targets forapproaches osteoporosis, using and na- closesnoparticles. with a discussion of potential therapeutic approaches using nanoparticles. FigureFigure 1.1. AA targeted, targeted, drug drug-bearing-bearing albumin albumin-based-based nanoparticle: nanoparticle: the the drug drug (siRNA; (siRNA; yellow yellow-green-green spi- spirals)rals) is incorporated is incorporated into into the the albumin albumin molecules molecules,, enabling enabling albumin albumin to toact act according according to toits its nature nature as the body´s main carrier for endogenous and exogenous substances in the blood. Each albumin is as the body’s main carrier for endogenous and exogenous substances in the blood. Each albumin connected via stable but still flexible linker molecules (pink spirals) to give the nanoparticle a thix- is connected via stable but still flexible linker molecules (pink spirals) to give the nanoparticle a otropic character important for transmembrane passage. The yellow Y-shaped molecules depict an- thixotropictibodies important character for important targeting. for transmembrane passage. The yellow Y-shaped molecules depict antibodies important for targeting. 2.2. TargetingTargeting TissuesTissues InIn Vivo Vivo Site-directedSite-directed targeting is is essential essential to to achieve achieve site site-directed-directed drug drug delivery. delivery. Present Present--day daytherapeutic therapeutic approaches approaches cannot cannot achieve achieve this. P this.reviously, Previously, we discussed we discussed the many the barriers many barriersthat must that be mustsurmounted be surmounted to achieve to target achieve access target from access the blood from or the from blood the orgastrointes- from the gastrointestinaltinal tract [11–13]. tract In [11 general,–13]. In peroral general, and peroral intravasal and intravasal routes of routes drug ofapplicatio drug applicationn are ex- aretremely extremely inefficient inefficient (efficiency (efficiency a fraction a fraction of 1%) of and 1%) have and have narrow narrow therapeutic therapeutic windows windows due dueto their to their multiple multiple and and serious serious side side effects effects [14 [–1416].–16 Application]. Application to tomucous mucous membranes membranes is isalmost almost equivalent equivalent to intravasal to intravasal application, application, the difference the difference being being the p theassage passage across across a thin aepithelium thin epithelium with narrow with narrow connective connective tissue tissuebetween