Methotrexate-loaded Fe-metal organic frameworks: Synthesis, characterizations, and drug release investigations

Cancer is a leading cause of death worldwide, affecting millions yearly [1,2] It is estimated that there will be over 20 million new cancer cases annually by 2030 [3]. Traditional cancer treatment methods, such as surgery, chemotherapy, and radiation therapy, have limitations, including weak targeting abilities and adverse side effects on healthy tissue. Drug delivery systems offer a promising solution to the aforementioned problems to achieve the desired therapeutic effects in humans or animals [4,5]. Drug delivery systems such as micelles or nanoparticles shield the drug from degradation and enable it to reach the target site in the body [6]. One of the major challenges in cancer treatment is the adverse side effects of anticancer drugs, which include anemia, tiredness, nausea, hepatotoxicity, nephrotoxicity, bone marrow suppression, mouth soreness, loss of appetite, hair loss, and skin changes. Moreover, direct delivery of anticancer drugs can also result in drug degradation before reaching the targeted site. Therefore, developing targeted drug delivery systems that can minimize side effects and improve therapeutic outcomes is critical.

Metal-organic frameworks (MOFs) have attracted enormous attention as drug delivery vehicles due to their excellent topology, adjustable pore size, high stability, and efficient drug-loading capacity [7]. Apart from drug delivery application, MOFs have also been used for photocatalysis [8,9], gas separation [10,11], heavy metal ions removal [12,13], and refrigeration [14]. Among various MOFs, the Fe-based MOFs such as Fe-BTC and MIL-53 Fe have been explored as anticancer drugs delivery vehicle, such as doxorubicin and oridonin, showing high loading efficiency and sustained release [15,16]. Studies have also shown that MOFs can serve as smart anticancer drug carriers by selecting appropriate metals and ligands. They are attractive owing to attributes including bioabsorbable, biodegradable, high drug loading capacity, delivery an appropriate amount of the respective drug to the cancer site, and showing minimum cytotoxicity to cancer cells [17,18]. Therefore, MOFs have great potential in targeted drug delivery systems for cancer treatment.

An anticancer drug methotrexate (MTX) belongs to the antimetabolites drug group. Methotrexate treats breast cancer [19], lymphoblastic leukemia [20], head and neck carcinoma [21], prostate and bladder cancer [22], osteosarcoma [23], and rheumatoid arthritis and psoriasis [24]. The side effects of MTX include hepatitis, kidney dysfunction, hyperglycemia [25]. MTX is a hepatotoxic drug that may cause cirrhosis and hepatitis [26]. As direct administration of MTX leads to severe side effects on human health, therefore the development of safe and biocompatible delivery system for MTX to minimize the side effects associated with its direct administration. MTX delivery to tumor tissue through polymeric micelles has already shown a sustained release of 76 % in 96 h [27]. However, to the best of our knowledge, Fe-MOF have not been explored as drug delivery vehicle for controlled release of MTX.

In this work, we report the synthesis and encapsulation of MIL-101-Fe with MTX for drug delivery studies. The MIL-101-Fe has shown an encapsulation efficiency of 84 % for MTX and a sustained release of 62 % in the first 50 h. It is pH-responsive, with the maximum drug release observed at pH 5.5, which is close to the requirement of tumor tissue. The drug release is mainly driven by diffusion, and the amount of drug release at pH 7.4 and pH 2.5 is negligible compared to that at pH 5.5, which can avoid premature drug release in normal cells and enhance drug release in the acidic environment of tumor tissue. Utilizing density functional theory (DFT) and time-dependent density functional theory (TD-DFT), three possible drug-MOF encapsulation complexes were explored. Among the DFT studied complexes, the complex with the drug molecule adsorbed at the carboxylate-bridge site of the carrier showed the highest binding energy of −59.90 with a polarizability value of 683.11 au and dipole moment of 4.85 Debye, which is much lower than the individual drug and MOF (10.84 and 21.39 Debye, respectively). The calculated band gap was also decreased during the encapsulation process. Thus, developing targeted drug delivery systems using MOFs offers a promising solution to the challenges of traditional cancer treatment methods. Further studies are needed to explore the potential of MOFs for use in clinical settings.

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