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      Drug delivery system for the extended-release of larotrectinib based on a biocompatible Fe-based metal-organic framework: synthesis, characterization, in vitro release properties and antitumor evaluation

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          Abstract

          Larotrectinib (Lar) is an orally administered tropomyosin receptor kinase (Trk) inhibitor with broad-spectrum antitumor activity that is available in clinical dosage forms as capsules and oral solutions. Currently, corresponding research is focused on developing new extended-release formulation systems for Lar. In this study, a biocompatible Fe-based metal-organic framework (Fe-MOF) carrier was synthesized by a solvent-based method, and a sustained-release drug delivery system (Lar@Fe-MOF) was constructed by nanoprecipitation and Lar loading. Lar@Fe-MOF was characterized by transmission electron microscopy (TEM), differential scanning calorimetry (DSC), fourier transform infrared (FTIR) spectroscopy, and thermogravimetric analysis (TGA), and its drug loading capacity and drug release properties were measured by ultraviolet–visible (UV–vis) spectroscopy. Then, the toxicity and biocompatibility of the Fe-MOF carriers were evaluated using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and hemocompatibility assays. Finally, the anticancer potential of Lar@Fe-MOF was investigated. The TEM results showed that Lar@Fe-MOF had a homogeneous fusiform nanostructural morphology. The DSC and FTIR results showed that Fe-MOF carriers were successfully synthesized and loaded with Lar, which was mainly in an amorphous form. Lar@Fe-MOF showed a large drug loading capacity (–10%) and significant slow-release properties in vitro. The MTT assay results showed that Lar@Fe-MOF had good dose-dependent anticancer activity. The in vivo pharmacodynamic assay results showed that Fe-MOF significantly increased the anticancer activity of Lar and was biocompatible. In conclusion, the Lar@Fe-MOF system developed in this study is a promising drug delivery platform because it is easy to manufacture, has high biocompatibility and ideal drug release and accumulation, can effectively eliminate tumors with improved safety and is expected to further expand therapeutic applications.

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          Polymer microspheres for controlled drug release.

          Andy Z. X. Zhu, Matthew S. Freiberg (2004)
          Polymer microspheres can be employed to deliver medication in a rate-controlled and sometimes targeted manner. Medication is released from a microsphere by drug leaching from the polymer or by degradation of the polymer matrix. Since the rate of drug release is controlled by these two factors, it is important to understand the physical and chemical properties of the releasing medium. This review presents the methods used in the preparation of microspheres from monomers or from linear polymers and discusses the physio-chemical properties that affect the formation, structure, and morphology of the spheres. Topics including the effects of molecular weight, blended spheres, crystallinity, drug distribution, porosity, and sphere size are discussed in relation to the characteristics of the release process. Added control over release profiles can be obtained by the employment of core-shell systems and pH-sensitive spheres; the enhancements presented by such systems are discussed through literature examples.
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            Metal–Organic Framework Nanocarriers for Drug Delivery in Biomedical Applications

            Yujia Sun, Liwei Zheng, Yu. Yang … (2020)
            Recent advances in biomedical applications of metal–organic framework (MOF) nanocarriers for drug delivery are summarized. State-of-the-art strategies to functionalize MOFs with therapeutic agents, as well as their merits and drawbacks, are comprehensively discussed. Investigation of metal–organic frameworks (MOFs) for biomedical applications has attracted much attention in recent years. MOFs are regarded as a promising class of nanocarriers for drug delivery owing to well-defined structure, ultrahigh surface area and porosity, tunable pore size, and easy chemical functionalization. In this review, the unique properties of MOFs and their advantages as nanocarriers for drug delivery in biomedical applications were discussed in the first section. Then, state-of-the-art strategies to functionalize MOFs with therapeutic agents were summarized, including surface adsorption, pore encapsulation, covalent binding, and functional molecules as building blocks. In the third section, the most recent biological applications of MOFs for intracellular delivery of drugs, proteins, and nucleic acids, especially aptamers, were presented. Finally, challenges and prospects were comprehensively discussed to provide context for future development of MOFs as efficient drug delivery systems.
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              Programmed Release of Dihydroartemisinin for Synergistic Cancer Therapy Using a CaCO 3 Mineralized Metal–Organic Framework

              Xiuyan Wan, Hui Zhong, Wei Pan … (2019)
              Dihydroartemisinin (DHA) has attracted increasing attention as an anticancer agent. However, using DHA to treat cancer usually depends on the synergistic effects of exogenous components, and the loss of DHA during delivery reduces its effectiveness in cancer therapy. Reported herein is a programmed release nanoplatform of DHA to synergistically treat cancer with a Fe-TCPP [(4,4,4,4-(porphine-5,10,15,20-tetrayl) tetrakis(benzoic acid)] NMOF (nanoscale MOF) having a CaCO3 mineralized coating, which prevents DHA leakage during transport in the bloodstream. When the nanoplatform arrives at the tumor site, the weakly acidic microenvironment and high concentration of glutathione (GSH) trigger DHA release and TCPP activation, enabling the synergistic Fe2+ -DHA-mediated chemodynamic therapy, Ca2+ -DHA-mediated oncosis therapy, and TCPP-mediated photodynamic therapy. In vivo experiments demonstrated that the nanoplatform showed enhanced anticancer efficiency and negligible toxicity.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Bioeng Biotechnol
                Journal ID (iso-abbrev): Front Bioeng Biotechnol
                Journal ID (publisher-id): Front. Bioeng. Biotechnol.
                Title: Frontiers in Bioengineering and Biotechnology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 2296-4185
                Publication date (Electronic): 01 June 2023
                Publication date Collection: 2023
                Volume: 11
                Electronic Location Identifier: 1197484
                Affiliations
                [1] 1 The Third Affiliated Hospital of Jinzhou Medical University , Jin Zhou, China
                [2] 2 Jiangsu Provincial Key Laboratory of Chiral Pharmaceutical Chemicals Biologically Manufacturing , College of Pharmacy and Chemistry & Chemical Engineering , Taizhou University , Taizhou, China
                [3] 3 The Affiliated Taixing People’s Hospital of Medical College , Yangzhou University , Yangzhou, China
                Author notes

                Edited by: Gang Chen, University of Health and Rehabilitation Sciences, China

                Reviewed by: Md. Rizwanullah, Jamia Hamdard University, India

                Xi Xu, China Pharmaceutical University, China

                Yanan Li, Nanjing Normal University, China

                *Correspondence: Yan-sheng Yao, yaoyansheng.yc@ 123456163.com ; Zhen-kun Ren, 2323193123@ 123456163.com
                [ † ]

                These authors have contributed equally to this work and share first authorship

                Article
                Publisher ID: 1197484
                DOI: 10.3389/fbioe.2023.1197484
                PMC ID: 10267385
                PubMed ID: 37324434
                SO-VID: 070b2b3d-cde8-4cdf-89db-801c0c39c547
                Copyright © Copyright © 2023 Gan, Ji, Zhang, Chen, Yao and Ren.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 31 March 2023
                Date accepted : 19 May 2023
                Funding
                This work was supported by the China Medical Hand-in-Hand Project Committee Beijing Medical Award Foundation Research Project (No. YXJL-2021-1093-0668), Major Projects of Liaoning Provincial Department of Education (JYTZD201912), Research Initiation Project of Taizhou Uni-versity (No. TZXY2020QDJJ009), Taizhou University 2022 Excellent Graduation Design (Thesis) Cul-tivation Program (No. 2023YP132).
                Categories
                Subject: Bioengineering and Biotechnology
                Subject: Original Research
                Custom metadata
                section-at-acceptance Nanobiotechnology

                Keywords: larotrectinib,metal-organic framework,slow release,biocompatible,antitumor
                Data availability:
                Keywords: larotrectinib, metal-organic framework, slow release, biocompatible, antitumor

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