Abstract
In the last decade, nanosized metal organic frameworks (NMOFs) have gained an increasing applicability as multifunctional nanocarriers for drug delivery in cancer therapy. However, only a limited number of platforms have been reported that can serve as an effective targeted drug delivery system (DDSs). Herein, we report rational design and construction of doxorubicin (DOX)-loaded nanoscale Zr (IV)-based NMOF (NH2-UiO-66) decorated with active tumor targeting moieties; folic acid (FA), lactobionic acid (LA), glycyrrhetinic acid (GA), and dual ligands of LA and GA, as efficient multifunctional DDSs for hepatocellular carcinoma (HCC) therapy. The success of modification was exhaustively validated by various structural, thermal and microscopic techniques. Biocompatibility studies indicated the safety of pristine NH2-UiO-66 against HSF cells whereas DOX-loaded dual-ligated NMOF was found to possess superior cytotoxicity against HepG2 cells which was further confirmed by flow cytometry. Moreover, fluorescence microscopy was used for monitoring cellular uptake in comparison to the non-ligated and mono-ligated NMOF. Additionally, the newly developed dual-ligated NMOF depicted a pH-responsiveness towards the DOX release. These findings open new avenues in designing various NMOF-based DDSs that actively target hepatic cancer to achieve precise therapy.
Highlights
In the last decade, nanosized metal organic frameworks (NMOFs) have gained an increasing applicability as multifunctional nanocarriers for drug delivery in cancer therapy
NH2-UiO-66 NMOF could be a promising candidate of drug delivery systems (DDSs) for effective multifunctional drug delivery because it exhibits several desirable characteristics. NH2-UiO-66 shows a high degree of connectivity in the crystal structure, providing outstanding chemical stability in a wide range of pHs in comparison with other Metal Organic Frameworks (MOFs)-based drug delivery carriers[23,24,25,26,27,28]
The high surface area and the large internal pores size which facilitate entrapment of large chemotherapeutics agents such as DOX, as well as its high biocompatibility, low toxicity and the ability to be scaled down to nanoscale (100–200 nm) which is suitable for chemotherapy s trategies[7], and the presence of amino group facilitates the surface modification[28] via covalent linking with small molecular targeting moieties, which are commonly used as targeting agents for HepG2 cells receptors[18,29]
Summary
In the last decade, nanosized metal organic frameworks (NMOFs) have gained an increasing applicability as multifunctional nanocarriers for drug delivery in cancer therapy. We report rational design and construction of doxorubicin (DOX)-loaded nanoscale Zr (IV)-based NMOF (NH2-UiO-66) decorated with active tumor targeting moieties; folic acid (FA), lactobionic acid (LA), glycyrrhetinic acid (GA), and dual ligands of LA and GA, as efficient multifunctional DDSs for hepatocellular carcinoma (HCC) therapy. The newly developed dual-ligated NMOF depicted a pH-responsiveness towards the DOX release These findings open new avenues in designing various NMOF-based DDSs that actively target hepatic cancer to achieve precise therapy. Active molecules could be incorporated into NMOFs structure through covalent bonds via one-pot synthesis or a post-synthesis modification These remarkable characteristics together with biocompatibility, low toxicity, and high loading capacity nominated NMOFs as potential platforms for various biological applications, especially as smart drug delivery vehicle for cancer t reatment[6,8,9]. It was hypothesized that adding more than one targeting ligand to NMOF surface could enhance its delivery and targeting performance to cancer cells
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