2000147 (1 of 13) © 2020 Wiley-VCH GmbH www.particle-journal.com FULL PAPER Facile Synthesis and Size Control of 2D Cyclodextrin-Based Metal–Organic Frameworks Nanosheet for Topical Drug Delivery Mubarak G. Bello, Yingchao Yang, Caifen Wang, Li Wu, Panpan Zhou, Huanyu Ding, Xiaofei Ge, Tao Guo, Lai Wei,* and Jiwen Zhang* DOI: 10.1002/ppsc.202000147 carrier system is delivering the active ingredient(s) to the target site of action in a safe, efective and efcient way to elicit its pharmacological efect. [1,2] Precisely, the drug should arrive at the disease site at the right time in a controlled manner. Topical eye formulations are the most convenient and accepted ocular delivery systems for treating eye dis- eases accounting for up to 90% of oph- thalmic medicines. [3] However, only 5% of the instilled dose penetrates into the deeper ocular tissues while the larger percentage gets lost through rapid eye blinking, tear turnover, and nasolacrimal drainage. Hence, making it extremely difcult to achieve therapeutic drug con- centration following topical eye instil- lation. [4] To overcome these challenges, numerous works have been reported in the literature and various strate- gies implemented to improve ocular bioavailability and retention time. [5–7] Several formulations and novel carrier systems have been designed, for example, in situ forming gel system, [8,9] microemul- sions, [10,11] and liposomes, [12,13] which are specifcally designed to achieve favorable residence time and sustained drug release. Though the use of these technologies has opened the door for more specifc and targeted delivery systems, the number of the novel ocular products entering into the market is very slow In this work, a 2D nanosheet (NS) of γ-cyclodextrin (CD)-based metal– organic frameworks (MOFs) is synthesized through a facile green chemistry approach. NS-MOF carrier is constructed using a water system in a simple one-pot reaction involving CD and potassium carbonate. Particle size opti- mization is achieved by adjusting the reaction temperature and the introduc- tion of crystal growth suppressor (appropriate proportion of acetone). The NS-MOF stability in aqueous medium is improved by polymerization reaction of crosslinked CD-MOF (CL-CD-MOF) without blocking its cavity for drug loading. The efects of particle geometry and size of nanoporous materials on their pharmacokinetics during drug delivery are compared between the sheet- like DXM@CL-NS-MOF and 3D-cubic-shaped DXM@CL-CD-MOF loaded with the same quantity of dexamethasone (DXM). The bioefciency of these carriers in tear fuids and aqueous humors to deliver DXM is investigated in vivo. The results demonstrate that the 2D-nanosheet particles signifcantly improve precorneal residence time and intraocular bioavailability over the commercial Maxidex (0.1% dexamethasone) and its 3D-cubes counterpart of similar chemical composition. It suggests that the geometry of a carrier play a signifcant role in the biodistribution, and the carrier of CL-NS-MOF is a good candidate for ocular drug delivery. 1. Introduction In the last decades, signifcant advancement has been made on ophthalmic drug delivery and yet there are many discrep- ancies and research void. The ultimate goal of every drug The ORCID identifcation number(s) for the author(s) of this article can be found under https://doi.org/10.1002/ppsc.202000147. M. G. Bello, Y. Yang, C. Wang, L. Wu, P. Zhou, H. Ding, T. Guo, Prof. J. Zhang Center for Drug Delivery Systems Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203, China E-mail: jwzhang@simm.ac.cn M. G. Bello, Y. Yang, Prof. J. Zhang School of Pharmacy University of Chinese Academy of Sciences Beijing 100049, China X. Ge, Prof. L. Wei State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat-sen University Guangzhou 510060, China E-mail: weil9@mail.sysu.edu.cn Prof. J. Zhang NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients National Institutes for Food and Drug Control No. 2 Tiantan Xili, Beijing 100050, China Part. Part. Syst. Charact. 2020, 2000147