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Abstract Chemoresistance and severe toxicities represent major drawbacks of chemotherapy. Natural extracts, including the essential oils of Pistacia lentiscus (PLEO), exhibit substantial anticancer and anti-inflammatory activities where different cancers are reported to dramatically recess following targeting with PLEO. PLEO has promising antimicrobial, anticancer, and anti-inflammatory properties. However, the therapeutic properties of PLEO are restricted by limited stability, bioavailability, and targeting ability. PLEO nanoformulation can maximize their physicochemical and therapeutic properties, overcoming their shortcomings. Hence, PLEO was extracted and its chemical composition was determined by GC–MS. PLEO and 5-Fluorouracil (5FU) were electrospun into poly-ε-caprolactone nanofibers (PCL-NFs), of 290.71 nm to 680.95 nm diameter, to investigate their anticancer and potential synergistic activities against triple-negative breast cancer cells (MDA-MB-231), human adenocarcinoma breast cancer cells (MCF-7), and human skin melanoma cell line (A375). The prepared nanofibers (NFs) showed enhanced thermal stability and remarkable physical integrity and tensile strength. Biodegradability studies showed prolonged stability over 42 days, supporting the NFs use as a localized therapy of breast tissues (postmastectomy) or melanoma. Release studies revealed sustainable release behaviors over 168 h, with higher released amounts of 5FU and PLEO at pH 5.4, indicating higher targeting abilities towards cancer tissues. NFs loaded with PLEO showed strong antioxidant properties. Finally, NFs loaded with either PLEO or 5FU depicted greater anticancer activities compared to free compounds. The highest anticancer activities were observed with NFs co-loaded with PLEO and 5FU. The developed 5FU-PLEO-PCL-NFs hold potential as a local treatment of breast cancer tissues (post-mastectomy) and melanoma to minimize their possible recurrence. Graphical Abstract

Ozonated olive oil (OL) combines the therapeutic effects of both ozone and olive oil. However, it suffers from limited water solubility and poor transdermal permeation, which hinder its application in melanoma treatment. Nanocarrier host molecules, such as niosomes, were used to improve the water solubility, transdermal permeation, and anticancer effect of hydrophobic compounds. This study aims to design and optimize a niosomal vesicular nanoplatform loaded with OL (OL/NSs) to improve OL’s skin permeation and anti-melanoma effect. In this regard, OL was prepared and characterized by evaluating its chemical properties (acid, peroxide, and iodine values) and fatty acid composition using gas chromatography. Then, OL/NSs were developed using the thin film hydration method employing cholesterol, Span 60, and Tween 60 at five different molar ratios. The optimized niosomes had an average diameter of 125.34 ± 13.29 nm, a surface charge of −11.34 ± 4.71 mV, and a spherical shape. They could entrap 87.30 ± 4.95% of the OL. OL/NSs showed a 75% sustained oil release over 24 h. The skin permeation percentage of OL/NSs was 36.78 ± 3.31 and 53.44 ± 6.41% at 12 and 24 h, respectively, three times higher than that of the free OL (11.50 ± 1.3 and 17.24 ± 2.06%, at 12 and 24 h, respectively). Additionally, the anticancer activity of the developed niosmal formulation, when tested on human melanoma cells (A375), was double that of the free OL; the IC50 of the OL/NSs was 8.63 ± 2.8 μg/mL, and that of the free OL was 17.4 ± 3.7 μg/mL. In conclusion, the encapsulation of ozonated olive oil in niosomes enhanced its water solubility, skin permeation, and anticancer activity and thus may represent potent natural chemotherapy in treating melanoma.

Para-sulfocalix[n]arenes are promising host molecules that can accommodate various chemotherapeutic drugs. Pt(IV)-based complexes, including satraplatin and asplatin, are promising alternatives that overcome the shortcomings of Pt(II) complexes. In this study, asplatin has been synthesized by fusing acetylsalicylic acid (aspirin) and cisplatin. Furthermore, it has been characterized using 1H NMR, mass spectrometry, elemental analysis, and UHPLC. A host-guest complex of asplatin and p-sulfocalix[4]arene (PSC4) has been developed and characterized using UV, Job’s plot analysis, HPLC, and density functional theory (DFT) calculations. The experimental and computational investigations propose that a 1:1 complex between asplatin and PSC4 is formed. The stability constant of the designed complex has been determined using Job’s plot and UHPLC and computed to be 9.1 × 104 M–1 and 8.7 × 104 M−1, which corresponds to a free energy of complexation of −6.8 kcal mol–1, while the calculated value for the inclusion free energy is −13.2 kcal mol−1. Both experimentally and theoretically estimated complexation free energy show that a stable host-guest complex can be formed in solution. The in vitro drug release study displayed the ability of the complex to release its cargo at a cancerous pH (pH of 5.5). Additionally, the asplatin/PSC4 complex is shown to be biocompatible when tested on human skin fibroblast noncancerous cells, demonstrating the highest in vitro cytotoxic activity against (MCF-7), cervical (HeLa), and lung cancer cells (A-549), with IC50 values of 0.75, 2.15, and 3.60 µg/mL, respectively. This is as compared to either cisplatin (IC50 of 5.47, 5.94 and 9.61 µg/mL, respectively) or asplatin (IC50 of 1.54, 5.05 and 3.91 µg/mL, respectively). On the other hand, the free asplatin exhibited higher cytotoxicity on cancerous cells and lower toxicity on noncancerous cells. The outcomes of the present joint theoretical and experimental investigation reinforce the interest in platinum-based anticancer therapeutics when they are protected from undesired interactions and suggest the use of the PSC4 macromolecule as a promising carrier for Pt(IV) anticancer drugs. The formed asplatin/PSC4 inclusion complex may represent an effective chemotherapeutic agent.

This study aims to design a pH-responsive dual-loaded nanosystem based on PEGylated chitosan nanoparticles loaded with ascorbic acid (AA) and oxaliplatin (OX) for the effective treatment of breast cancer. In this regard, non-PEGylated and PEGylated chitosan nanoparticles (CS NPs) loaded with either ascorbic acid (AA), oxaliplatin (OX), or dual-loaded with AA-OX were fabricated using the ionotropic gelation method. The hydrodynamic diameters of the fabricated AA/CS NPs, OX/CS NPs, and AA-OX/CS NPs were 157.20 ± 2.40, 188.10 ± 9.70, and 261.10 ± 9.19 nm, respectively. While the hydrodynamic diameters of the designed AA/PEG-CS NPs, OX/PEG-CS NPs, and AA-OX/PEG-CS NPs were 152.20 ± 2.40, 156.60 ± 4.82, and 176.00 ± 4.21 nm, respectively. The ζ-potential of the prepared nanoparticles demonstrated high positive surface charges of +22.02 ± 1.50, +22.58 ± 1.85 and +40.4 ± 2.71 mV for AA/CS NPs, OX/CS NPs, and AA-OX/CS NPs, respectively. The ζ-potential of the PEGylated CS NPs was reduced owing to the shielding of the positive charges by the PEG chains. Additionally, all the prepared nanoparticles exhibited high entrapment efficiencies (EE%) and spherical-shaped morphology. The chemical features of the prepared nanoparticles were investigated using Fourier transform infrared (FTIR) spectroscopy. Release studies showed the capability of the prepared non-PEGylated and PEGylated chitosan NPs to release their cargo in the acidic environment of cancer tissue (pH 5.5). Furthermore, the AA/CS NPs, AA/PEG-CS NPs, OX/CS NPs, OX/PEG-CS NPs, AA-OX/CS NPs and AA-OX/PEG-CS NPs exhibited remarkable cytotoxic activities against breast adenocarcinoma (MCF-7) cells with IC50 values of 44.87 ± 11.49, 23.3 ± 3.73, 23.88 ± 6.29, 17.98 ± 3.99, 18.69 ± 2.22, and 7.5 ± 0.69 µg/mL, respectively; as compared to free AA and OX (IC50 of 150.80 ± 26.50 and 147.70 ± 63.91 µg/mL, respectively). Additionally, treatment of MCF-7 cells with IC50 concentrations of AA, AA/CS NPs, AA/PEG-CS NPs, OX, OX/CS NPs, OX/PEG-CS NPs, AA-OX/CS NPs or AA-OX/PEG-CS NPs increased the percentages of early apoptotic cells to 5.28%, 9.53%, 11.20%, 5.27%, 13.80%, 8.43%, 2.32%, and 10.10%, respectively, and increased the percentages of late apoptotic cells to 0.98%, 0.37%, 2.41%, 2.06%, 0.97%, 9.66%, 56%, and 81.50%, respectively. These results clearly indicate that PEGylation enhances the apoptotic effect of AA and OX alone, in addition to potentiating the apoptotic effect of AA and OX when combined on MCF-7 cells. In conclusion, PEGylated chitosan nanoparticles encapsulating AA, OX, or AA and OX represent an effective formula for induction of apoptosis in MCF-7 cells.

Marine algae are a rich source of biologically active compounds that can be utilized in various food and pharmaceutical applications. In this study, ultrasound-assisted extraction (UAE) was optimized to maximize yield and total carbohydrate content extracted from the red algae, Pterocladia capillacea. The extract was shown to possess potent antioxidant activity of up to ~70%, and was successfully used as a reducing and capping agent in the green synthesis of copper nanoparticles, which were characterized by UV-spectroscopy, Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), transmission electron microscopy (TEM), and dynamic light scattering (DLS). Primarily, CuO nanoparticles with an average size of 62 nm were produced. FTIR spectra for the extract and algal-mediated CuO nanoparticles showed characteristic polysaccharide peaks. The synthesized CuO nanoparticles were subsequently loaded with nedaplatin where UV data suggested a complex formation. Nedaplatin release profiles showed a sustained release that reached a maximum at 120 h. The formulation was shown to have greater cytotoxicity relative to nedaplatin on hepatocellular carcinoma, breast cancer and ovarian cancer cell lines with IC50 values of 0.40 ± 0.08, 1.50 ± 0.12, and 0.70 ± 0.09 µg/mL, respectively. Loading nedaplatin onto CuO nanoparticles synthesized using red algae extract, greatly enhances its anticancer effect.

Antimicrobial drugs face numerous challenges, including drug resistance, systemic toxic effects, and poor bioavailability. To date, treatment choices are limited, which warrants the search for novel potent antivirals, including those extracted from natural products. The seeds of Peganum harmala L. (Zygophyllaceae family) have been reported to have antimicrobial, antifungal, and anticancer activities. In the present study, a 2-hydroxy propyl-β-cyclodextrin (HPβCD)/harmala alkaloid-rich fraction (HARF) host–guest complex was prepared using a thin-film hydration method to improve the water solubility and bioavailability of HARF. The designed complex was then co-encapsulated with ascorbic acid into PLGA nanoparticles coated with polyethylene glycol (HARF–HPßCD/AA@PLGA-PEG NPs) using the W/O/W multiple emulsion-solvent evaporation method. The average particle size, PDI, and zeta potential were 207.90 ± 2.60 nm, 0.17 ± 0.01, and 31.6 ± 0.20 mV, respectively. The entrapment efficiency for HARF was 81.60 ± 1.20% and for ascorbic acid was 88 ± 2.20%. HARF–HPßCD/AA@PLGA-PEG NPs had the highest antibacterial activity against Staphylococcus aureus and Escherichia coli (MIC of 0.025 mg/mL). They also exhibited high selective antiviral activity against the H1N1 influenza virus (IC50 2.7 μg/mL) without affecting the host (MDCK cells). In conclusion, the co-encapsulation of HPCD–HARF complex and ascorbic acid into PLGA-PEG nanoparticles significantly increased the selective H1N1 killing activity with minimum host toxic effects.

Wound healing is a major healthcare concern, and complicated wounds may lead to severe outcomes such as septicemia and amputations. To date, management choices are limited, which warrants the search for new potent wound healing agents. Natural products loaded in poly (lactic-co-glycolic acid) (PLGA) coated with chitosan (CS) constitute a promising antibacterial wound healing formulation. In this work, harmala alkaloid-rich fraction (HARF) loaded into PLGA nanoparticles coated with chitosan (H/CS/PLGA NPs) were designed using the emulsion-solvent evaporation method. Optimization of the formulation variables (HARF: PLGA and CS: PLGA weight ratios, sonication time) was performed using the 33 Box–Behnken design (BBD). The optimal NPs were characterized using transmission electron microscopy (TEM) and Attenuated Total Reflection Fourier-Transformed Infrared Spectroscopy (ATR-FTIR). The prepared NPs had an average particle size of 202.27 ± 2.44 nm, a PDI of 0.23 ± 0.01, a zeta potential of 9.22 ± 0.94 mV, and an entrapment efficiency of 86.77 ± 4.18%. In vitro drug release experiments showed a biphasic pattern where an initial burst of 82.50 ± 0.20% took place in the first 2 h, which increased to 87.50 ± 0.50% over 72 h. The designed optimal H/CS/PLGA NPs exerted high antibacterial activity against Staphylococcus aureus and Escherichia coli (MIC of 0.125 and 0.06 mg/mL, respectively) compared to unloaded HARF (MIC of 0.50 mg/mL). The prepared nanoparticles were found to be biocompatible when tested on human skin fibroblasts. Moreover, the wound closure percentage after 24 h of applying H/CS/PLGA NPs was found to be 94.4 ± 8.0%, compared to free HARF and blank NPs (68.20 ± 5.10 and 50.50 ± 9.40%, respectively). In conclusion, the three components of the developed nanoformulation (PLGA, chitosan, and HARF) have synergistic antibacterial and wound healing properties for the management of infected wounds.

Photodynamic therapy (PDT) is a promising non-invasive strategy in the fight against that which circumvents the systemic toxic effects of chemotherapeutics. It relies on photosensitizers (PSs), which are photoactivated by light irradiation and interaction with molecular oxygen. This generates highly reactive oxygen species (such as 1O2, H2O2, O2, ·OH), which kill cancer cells by necrosis or apoptosis. Despite the promising effects of PDT in cancer treatment, it still suffers from several shortcomings, such as poor biodistribution of hydrophobic PSs, low cellular uptake, and low efficacy in treating bulky or deep tumors. Hence, various nanoplatforms have been developed to increase PDT treatment effectiveness and minimize off-target adverse effects. Liposomes showed great potential in accommodating different PSs, chemotherapeutic drugs, and other therapeutically active molecules. Here, we review the state-of-the-art in encapsulating PSs alone or combined with other chemotherapeutic drugs into liposomes for effective tumor PDT.

This study reports a facile and eco-friendly method for the green synthesis of platinum and palladium nanoparticles (Pt NPs and Pd NPs) using Peganum harmala seed alkaloid fraction. The ζ-potential of the synthesized Pt NPs, Pd NPs and Pt–Pd NPs were −11.2 ± 0.5, −9.7 ±1.2, and −12.7 ± 2.1 mV; respectively. Transmission electron microscopy (TEM) revealed the formation of spherical-shaped nanoparticles with smooth margins. The mean diameters of the synthesized Pt NPs, Pd NPs, and Pt–Pd NPs were determined using TEM analysis and were found to be 20.3 ± 1.9, 22.5 ± 5.7, and 33.5 ± 5.4 nm, respectively. The nanoparticles’ bioreduction was confirmed by ultraviolet–visible (UV–vis) spectroscopy, X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy, and their organic contents were determined by thermal gravimetric analysis (TGA). The Pt–Pd NPs mixture showed more pronounced antioxidant activity of 843.0 ± 60 μM Trolox equivalent (TE)/mg NPs compared to the individual Pt NPs (277.3 ± 13.5 μM TE/mg NPs) and Pd NPs (167.6 ± 4.8 μM TE/mg NPs). Furthermore, the Pt–Pd NPs exhibited significant cytotoxic activities against lung cancer (A549) and breast adenocarcinoma (MCF-7) cells, IC50 of 8.8 and 3.6 µg/mL, respectively; as compared to Pt NPs (IC50 of 10.9 and 6.7 µg/mL, respectively) and Pd NPs (IC50 of 31 and 10.8 µg/mL, respectively and compared to carboplatin (IC50 of 23 and 9.5 µg/mL, respectively). Moreover, molecular docking studies were conducted to explore the possible anticancer and antioxidant mechanisms of the biogenic nanoparticles. Pt NPs, Pd NPs, and their mixture showed inhibitory activity against cysteine proteinase, which supports their high antitumor activity, but moderate antioxidant activity. In conclusion, Pd-Pt NPs mixture prepared using harmala seed alkaloid fraction showed potential as effective antineoplastic agents.

P-sulfonatocalix[n]arenes have demonstrated a great potential for encapsulation of therapeutic drugs via host-guest complexation to improve solubility, stability, and bioavailability of encapsulated drugs. In this work, guest-host complexes of a third-generation anticancer drug (oxaliplatin) and p-4-sulfocalix[n]arenes (n = 4 and 6; p-SC4 and p-SC6, respectively) were prepared and investigated, using 1H NMR, UV, Job’s plot analysis, and DFT calculations, for use as cancer therapeutics. The peak amplitude of the prepared host-guest complexes was linearly proportional to the concentration of oxaliplatin in the range of 1.0 × 10−5 M−1 to 2.1 × 10−4 M−1. The reaction stoichiometry between either p-SC4 or p-SC6 and oxaliplatin in the formed complexes was 1:1. The stability constants for the complexes were 5.07 × 104 M−1 and 6.3 × 104 M−1. These correspond to complexation free energy of −6.39 and −6.52 kcal/mol for p-SC4 and p-SC6, respectively. Complexation between oxaliplatin and p-SC4 or p-SC6 was found to involve hydrogen bonds. Both complexes exhibited enhanced biological and high cytotoxic activities against HT-29 colorectal cells and MCF-7 breast adenocarcinoma compared to free oxaliplatin, which warrants further investigation for cancer therapy.

Platinum nanoparticles (PtNPs) have superior physicochemical properties and great potential in biomedical applications. Eco-friendly and economic approaches for the synthesis of PtNPs have been developed to overcome the shortcomings of the traditional physical and chemical methods. Various biogenic entities have been utilized in the green synthesis of PtNPs, including mainly plant extracts, algae, fungi bacteria, and their biomedical effects were assessed. Other biological derivatives have been used in the synthesis of PtNPs such as egg yolk, sheep milk, honey, and bovine serum albumin protein. The green approaches for the synthesis of PtNPs have reduced the reaction time, the energy required, and offered ambient conditions of fabrication. This review highlights the state-of-the-art methods used for green synthesis of PtNPs, synthesis parameters, and their reported biomedical applications.