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  1. Yusefi M, Shameli K, Su Yee O, Teow SY, Hedayatnasab Z, Jahangirian H, et al.
    Int J Nanomedicine, 2021;16:2515-2532.
    PMID: 33824589 DOI: 10.2147/IJN.S284134
    INTRODUCTION: Fe3O4 nanoparticles (Fe3O4 NPs) with multiple functionalities are intriguing candidates for various biomedical applications.

    MATERIALS AND METHODS: This study introduced a simple and green synthesis of Fe3O4 NPs using a low-cost stabilizer of plant waste extract rich in polyphenols content with a well-known antioxidant property as well as anticancer ability to eliminate colon cancer cells. Herein, Fe3O4 NPs were fabricated via a facile co-precipitation method using the crude extract of Garcinia mangostana fruit peel as a green stabilizer at different weight percentages (1, 2, 5, and 10 wt.%). The samples were analyzed for magnetic hyperthermia and then in vitro cytotoxicity assay was performed.

    RESULTS: The XRD planes of the samples were corresponding to the standard magnetite Fe3O4 with high crystallinity. From TEM analysis, the green synthesized NPs were spherical with an average size of 13.42±1.58 nm and displayed diffraction rings of the Fe3O4 phase, which was in good agreement with the obtained XRD results. FESEM images showed that the extract covered the surface of the Fe3O4 NPs well. The magnetization values for the magnetite samples were ranging from 49.80 emu/g to 69.42 emu/g. FTIR analysis verified the functional groups of the extract compounds and their interactions with the NPs. Based on DLS results, the hydrodynamic sizes of the Fe3O4 nanofluids were below 177 nm. Furthermore, the nanofluids indicated the zeta potential values up to -34.92±1.26 mV and remained stable during four weeks of storage, showing that the extract favorably improved the colloidal stability of the Fe3O4 NPs. In the hyperthermia experiment, the magnetic nanofluids showed the acceptable specific absorption rate (SAR) values and thermosensitive performances under exposure of various alternating magnetic fields. From results of in vitro cytotoxicity assay, the killing effects of the synthesized samples against HCT116 colon cancer cells were mostly higher compared to those against CCD112 colon normal cells. Remarkably, the Fe3O4 NPs containing 10 wt.% of the extract showed a lower IC50 value (99.80 µg/mL) in HCT116 colon cancer cell line than in CCD112 colon normal cell line (140.80 µg/mL).

    DISCUSSION: This research, therefore, introduced a new stabilizer of Garcinia mangostana fruit peel extract for the biosynthesis of Fe3O4 NPs with desirable physiochemical properties for potential magnetic hyperthermia and colon cancer treatment.

  2. Yusefi M, Shameli K, Jahangirian H, Teow SY, Afsah-Hejri L, Mohamad Sukri SNA, et al.
    Int J Nanomedicine, 2023;18:3535-3575.
    PMID: 37409027 DOI: 10.2147/IJN.S375964
    Chemotherapy is the most prominent route in cancer therapy for prolonging the lifespan of cancer patients. However, its non-target specificity and the resulting off-target cytotoxicities have been reported. Recent in vitro and in vivo studies using magnetic nanocomposites (MNCs) for magnetothermal chemotherapy may potentially improve the therapeutic outcome by increasing the target selectivity. In this review, magnetic hyperthermia therapy and magnetic targeting using drug-loaded MNCs are revisited, focusing on magnetism, the fabrication and structures of magnetic nanoparticles, surface modifications, biocompatible coating, shape, size, and other important physicochemical properties of MNCs, along with the parameters of the hyperthermia therapy and external magnetic field. Due to the limited drug-loading capacity and low biocompatibility, the use of magnetic nanoparticles (MNPs) as drug delivery system has lost traction. In contrast, MNCs show higher biocompatibility, multifunctional physicochemical properties, high drug encapsulation, and multi-stages of controlled release for localized synergistic chemo-thermotherapy. Further, combining various forms of magnetic cores and pH-sensitive coating agents can generate a more robust pH, magneto, and thermo-responsive drug delivery system. Thus, MNCs are ideal candidate as smart and remotely guided drug delivery system due to a) their magneto effects and guide-ability by the external magnetic fields, b) on-demand drug release performance, and c) thermo-chemosensitization under an applied alternating magnetic field where the tumor is selectively incinerated without harming surrounding non-tumor tissues. Given the important effects of synthesis methods, surface modifications, and coating of MNCs on their anticancer properties, we reviewed the most recent studies on magnetic hyperthermia, targeted drug delivery systems in cancer therapy, and magnetothermal chemotherapy to provide insights on the current development of MNC-based anticancer nanocarrier.
  3. Yusefi M, Chan HY, Teow SY, Kia P, Lee-Kiun Soon M, Sidik NABC, et al.
    Nanomaterials (Basel), 2021 Jun 28;11(7).
    PMID: 34203241 DOI: 10.3390/nano11071691
    Cellulose and chitosan with remarkable biocompatibility and sophisticated physiochemical characteristics can be a new dawn to the advanced drug nano-carriers in cancer treatment. This study aims to synthesize layer-by-layer bionanocomposites from chitosan and rice straw cellulose encapsulated 5-Fluorouracil (CS-CF/5FU BNCs) using the ionic gelation method and the sodium tripolyphosphate (TPP) cross-linker. Data from X-ray and Fourier-transform infrared spectroscopy showed successful preparation of CS-CF/5FU BNCs. Based on images of scanning electron microscopy, 48.73 ± 1.52 nm was estimated for an average size of the bionanocomposites as spherical chitosan nanoparticles mostly coated rod-shaped cellulose reinforcement. 5-Fluorouracil indicated an increase in thermal stability after its encapsulation in the bionanocomposites. The drug encapsulation efficiency was found to be 86 ± 2.75%. CS-CF/5FU BNCs triggered higher drug release in a media simulating the colorectal fluid with pH 7.4 (76.82 ± 1.29%) than the gastric fluid with pH 1.2 (42.37 ± 0.43%). In in vitro cytotoxicity assays, cellulose fibers, chitosan nanoparticles and the bionanocomposites indicated biocompatibility towards CCD112 normal cells. Most promisingly, CS-CF/5FU BNCs at 250 µg/mL concentration eliminated 56.42 ± 0.41% of HCT116 cancer cells and only 8.16 ± 2.11% of CCD112 normal cells. Therefore, this study demonstrates that CS-CF/5FU BNCs can be considered as an eco-friendly and innovative nanodrug candidate for potential colorectal cancer treatment.
  4. Yusefi M, Shameli K, Jahangirian H, Teow SY, Umakoshi H, Saleh B, et al.
    Int J Nanomedicine, 2020;15:5417-5432.
    PMID: 32801697 DOI: 10.2147/IJN.S250047
    INTRODUCTION: Green-based materials have been increasingly studied to circumvent off-target cytotoxicity and other side-effects from conventional chemotherapy.

    MATERIALS AND METHODS: Here, cellulose fibers (CF) were isolated from rice straw (RS) waste by using an eco-friendly alkali treatment. The CF network served as an anticancer drug carrier for 5-fluorouracil (5-FU). The physicochemical and thermal properties of CF, pure 5-FU drug, and the 5-FU-loaded CF (CF/5-FU) samples were evaluated. The samples were assessed for in vitro cytotoxicity assays using human colorectal cancer (HCT116) and normal (CCD112) cell lines, along with human nasopharyngeal cancer (HONE-1) and normal (NP 460) cell lines after 72-hours of treatment.

    RESULTS: XRD and FTIR revealed the successful alkali treatment of RS to isolate CF with high purity and crystallinity. Compared to RS, the alkali-treated CF showed an almost fourfold increase in surface area and zeta potential of up to -33.61 mV. SEM images illustrated the CF network with a rod-shaped structure and comprised of ordered aggregated cellulose. TGA results proved that the thermal stability of 5-FU increased within the drug carrier. Based on UV-spectroscopy measurements for 5-FU loading into CF, drug loading encapsulation efficiency was estimated to be 83 ±0.8%. The release media at pH 7.4 and pH 1.2 showed a maximum drug release of 79% and 46%, respectively, over 24 hours. In cytotoxicity assays, CF showed almost no damage, while pure 5-FU killed most of the both normal and cancer cells. Impressively, the drug-loaded sample of CF/5-FU at a 250 µg/mL concentration demonstrated a 58% inhibition against colorectal cancer cells, but only a 23% inhibition against normal colorectal cells. Further, a 62.50 µg/mL concentration of CF/5FU eliminated 71% and 39% of nasopharyngeal carcinoma and normal nasopharyngeal cells, respectively.

    DISCUSSION: This study, therefore, showed the strong potential anticancer activity of the novel CF/5-FU formulations, warranting their further investigation.

  5. Yusefi M, Nasef MM, Tareq MA, Gupta B, Shameli K, Ali RR, et al.
    Polymers (Basel), 2022 Nov 10;14(22).
    PMID: 36432958 DOI: 10.3390/polym14224831
    Functional polymeric biomaterials (FPBMs) with bioactive characteristics obtained by radiation-induced graft copolymerisation (RIGC) have been subjected to intensive research and developed into many commercial products. Various studies have reported the development of a variety of radiation-grafted FPBMs. However, no reports dealing with the quantitative evaluations of these studies from a global bibliographic perspective have been published. Such bibliographic analysis can provide information to overcome the limitations of the databases and identify the main research trends, together with challenges and future directions. This review aims to provide an unprecedented bibliometric analysis of the published literature on the use of RIGC for the preparation of FPBMs and their applications in medical, biomedical, biotechnological, and health care fields. A total of 235 publications obtained from the Web of Science (WoS) in the period of 1985-2021 were retrieved, screened, and evaluated. The records were used to manifest the contributions to each field and underline not only the top authors, journals, citations, years of publication, and countries but also to highlight the core research topics and the hubs for research excellence on these materials. The obtained data overviews are likely to provide guides to early-career scientists and their research institutions and promote the development of new, timely needed radiation-grafted FPBMs, in addition to extending their applications.
  6. Yusefi M, Shameli K, Lee-Kiun MS, Teow SY, Moeini H, Ali RR, et al.
    Int J Biol Macromol, 2023 Apr 01;233:123388.
    PMID: 36706873 DOI: 10.1016/j.ijbiomac.2023.123388
    Polysaccharide-based magnetic nanocomposites can eminently illuminate several attractive features as anticancer drug carriers. In this study, rice straw-based cellulose nanowhisker (CNW) was used as solid support for Fe3O4 nanofillers to synthesize magnetic CNW. Then, cross-linked chitosan-coated magnetic CNW for 5-fluorouracil carrier abbreviated as CH/MCNW/5FU. Fourier-transform infrared, X-Ray diffraction, and X-ray photoelectron spectroscopy analysis indicated successful fabrication and multifunctional properties of the CH/MCNW/5FU nanocomposites. In addition, CH/MCNW/5FU nanocomposites showed hydrodynamic diameter and zeta potential value of 181.31 ± 3.46 nm and +23 ± 1.8 mV, respectively. Based on images of transmission electron microscopy, magnetic CNW as reinforcement was coated with chitosan to obtain almost spherical CH/MCNW/5FU nanocomposites with an average diameter of 37.16 ± 3.08. The nanocomposites indicated desired saturation magnetization and thermal stability, high drug encapsulation efficiency, and pH-dependent swelling and drug release performance. CH/MCNW/5FU nanocomposites showed potent killing effects against colorectal cancer cells in both 2D monolayer and 3D spheroid models. These findings suggest CH/MCNW as a potential carrier for anticancer drugs with high tumour-penetrating capacity.
  7. Yusefi M, Lee-Kiun MS, Shameli K, Teow SY, Ali RR, Siew KK, et al.
    Carbohydr Polym, 2021 Dec 01;273:118523.
    PMID: 34560940 DOI: 10.1016/j.carbpol.2021.118523
    Magnetic polymer nanocomposites are inherently multifunctional and harbor assorted physiochemical actions for applications thereof as novel drug nanocarriers. Herein, Fe3O4-nanoparticles were supported on rice straw cellulose for 5-fluorouracil carrier abbreviated as MC/5-FU for potential colorectal cancer treatments. Several analyses indicated the multifunctional properties of MC/5-FU bionanocomposites. Transmission and scanning electron microscopy study demonstrated that Fe3O4 nanofillers covered the cellulose matrix. The drug release from MC/5-FU was evaluated under various pH and temperature conditions, showing the maximum release at pH 7.4 and 44.2 °C. In in vitro anticancer assay, MC/5-FU exhibited enhanced selectivity and anticancer actions against 2D monolayer and 3D tumour spheroid models colorectal cancer cells. The anticancer effects of MC/5-FU with magnetic targeting and heat induction were also examined. This easily synthesized MC/5-FU indicated the potential in application as a low-cost drug formulation for colorectal cancer treatments.
  8. Yusefi M, Soon ML, Teow SY, Monchouguy EI, Neerooa BNHM, Izadiyan Z, et al.
    Int J Biol Macromol, 2022 Feb 28;199:372-385.
    PMID: 34998882 DOI: 10.1016/j.ijbiomac.2021.12.189
    Polysaccharide nanocrystals have great potential to be used as improved drug carriers due to their low cost, high biodegradability, and biocompatibility. This study reports the synthesis of cellulose nanocrystals (CNC) loaded with 5-fluorouracil (CNC/5FU) to evaluate their anticancer activity against colorectal cancer cells. X-ray and Fourier-transform infrared spectroscopy demonstrated that acid hydrolysis successfully degraded the amorphous cellulose to liberate the crystal regions. From transmission electron microscopy, CNC/5FU appeared as rod-like nanocrystals with an average length and width of 69.53 ± 1.14 nm and 8.13 ± 0.72 nm, respectively. The anticancer drug 5FU showed improved thermal stability after being loading onto CNC. From UV-vis spectroscopy data, the drug encapsulation efficiency in CNC/5FU was estimated to be 83.50 ± 1.52%. The drug release of CNC/5FU was higher at pH 7.4 compared to those at pH 4.2 and 1.2. From the cytotoxicity assays, CNC did not affect the viability of CCD112 colon normal cells. On the other hand, CNC/5FU exhibited anticancer effects against HCT116 and HT-29 colorectal cancer cells. The anticancer actions of CNC/5FU against HCT116 cells were then confirmed using an in vitro tumor-on-chip model and clonogenic assay. Mechanistic studies demonstrated that CNC/5FU killed the cancer cells by mainly inducing cell apoptosis and mitochondrial membrane damage. Overall, this study indicated that CNC/5FU could be a potential nanoformulation for improved drug delivery and colorectal cancer treatment.
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