Development of Mitoxantrone-Loaded Quercetin Nanoparticles for Breast Cancer Therapy with Potential for Synergism with Bioactive Natural Products.

Nanoparticle (NP)-based drug delivery systems have caused a paradigm shift in cancer treatment by enabling drug targeting, sustaining drug release, and reducing systemic toxicity of chemotherapy. Here we developed a novel NP formulation for the anticancer drug mitoxantrone (MTZ) by loading it into an emerging nanomaterial derived from the plant polyphenol quercetin (QCT). QCT was partially oxidized to produce amphiphilic oxQCT which was co-assembled with poly(ethylene glycol) (PEG) and MTZ by nanoprecipitation to form MTZ NPs. The optimal NPs exhibited an average diameter of 128 nm, a polydispersity index of 0.22, and a drug loading efficiency of 76%. While only a small fraction of the loaded drug was released at physiologic pH, a significantly higher fraction was released at acidic pH. The anticancer activity of MTZ NPs was assessed in MCF-7 and MDA-MB-231 breast cancer cell lines, alone and in combination with the bioactive natural products curcumin (CUR) and thymoquinone (TQ). In cell viability assays, MTZ NPs were slightly less potent than free MTZ, most likely due to their sustained release properties, but their cytotoxicity was greatly enhanced in the presence of TQ (in MCF-7 cells) as well as CUR (in MDA-MB-231 cells). The results were corroborated by apoptosis assays such as mitochondrial membrane potential measurement, acridine orange/ethidium bromide staining, in addition to caspase activity assays. The assays revealed that the NPs' proapoptotic effect was enhanced in the presence of CUR or TQ, depending on the cell line. Our work presents a promising nanocarrier platform for MTZ with the potential to enhance its bioactivity against breast cancer when combined with bioactive natural products.

A Hydrogen-Bonded Organic Framework Equipped with a Molecular Nanovalve.

The concept of a molecular nanovalve is applied to a synthesized biocompatible hydrogen-bonded organic framework (HOF), termed RSS-140, to load, trap, and subsequently release an antioxidant on command. Specifically, we exploit the pore windows of RSS-140 (i.e., ß-CD cavities) to first load and trap the antioxidant, Trolox, within the internal pores of the HOF (Trolox⊂RSS-140) and, to prevent it from leaching, utilize supramolecular chemistry to complex azobenzene (Azo) with ß-CD (Trolox⊂Azo@RSS-140). The molecular nanovalve is fully realized upon exposing Trolox⊂Azo@RSS-140 to UV light with a specific wavelength, which induces Azo isomerization, Azo decomplexation from ß-CD, and subsequent release of Trolox from the pores of RSS-140. The biocompatibility and nontoxicity of Trolox⊂Azo@RSS-140, together with the absolute control over the nanovalve opening, were established to yield a system that safely and slowly releases Trolox for longer-lasting antioxidant efficacy. As the field of supramolecular chemistry is rich with similar systems and many such systems can be used as building blocks to construct HOFs or other extended framework materials, we envision the molecular nanovalve concept to be applied widely for controllably delivering molecular cargo for diverse applications.

Identifying synergistic combinations of Doxorubicin-Loaded polyquercetin nanoparticles and natural Products: Implications for breast cancer therapy.

Combining chemotherapeutic agents with bioactive natural products is an attractive cancer treatment modality to reduce the dose and side effects of chemotherapy. Combination treatments with drugs having different mechanisms of action can also be beneficial in combatting the development of drug resistance by cancer cells. Nanoparticle (NP)-mediated drug delivery can further improve the therapeutic index of cytotoxic agents by enabling passive and/or active targeting to tumor tissues in vivo. Using doxorubicin (DOX) as a model chemotherapeutic agent, we developed three NP formulations based on polyquercetin (pQCT), an emerging nanocarrier platform. The NPs were co-assembled with DOX, pQCT, and either Pluronic P123, methoxy poly(ethylene glycol)-amine, or D-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS). Physicochemical characterization of the NPs revealed them to have a spherical morphology with high monodispersity, excellent drug loading capacity, and sustained drug release. Then, the NPs were evaluated in vitro to determine their potential synergism when combined with the bioactive natural products curcumin (CUR), tannic acid (TA), and thymoquinone (TQ) against breast cancer cells (MCF-7 and MDA-MB-231). Surprisingly, most of the combinations were found to be antagonistic. However, combinations containing CUR exhibited greater pro-apoptotic effects compared to the single agents, with polymer-modified pQCT NPs presenting as a promising nanoplatform for enhancing DOX's ability to promote cancer cell apoptosis. Our findings provide insights into the potential application of pQCT in nanomedicine, as well as the use of bioactive natural products in combination with DOX as a free agent and as an NP formulation in the treatment of breast cancer.

Vitamin E TPGS-Poloxamer Nanoparticles Entrapping a Novel PI3Kα Inhibitor Potentiate Its Activity against Breast Cancer Cell Lines.

N-(2-fluorphenyl)-6-chloro-4-hydroxy-2-quinolone-3-carboxamide (R19) is a newly synthesized phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitor with promising activity against cancer cells. The purpose of this study was to develop a polymeric nanoparticle (NP) formulation for R19 to address its poor aqueous solubility and to facilitate its future administration in preclinical and clinical settings. NPs were prepared by nanoprecipitation using two polymers: D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) and the poloxamer Pluronic P123 in different ratios. Physicochemical characterization of the NPs revealed them to be around 100 nm in size with high monodispersity, a spherical morphology, and an almost neutral surface charge. The NPs achieved ~60% drug loading efficiency and sustained release of R19 for up to 96 h, with excellent colloidal stability in serum-containing cell culture media. NPs containing TPGS enhanced R19's potency against MCF-7 and MDA-MB-231 breast cancer cells in vitro, with half-maximal inhibitory concentrations (IC50) ranging between 1.8 and 4.3 µM compared to free R19, which had an IC50 of 14.7-17.0 µM. The NPs also demonstrated low cytotoxicity against human dermal fibroblasts and more significant induction of apoptosis compared to the free drug, which was correlated with their cellular uptake efficiency. Our findings present a biocompatible NP formulation for the delivery of a cancer-targeted PI3Kα inhibitor, R19, which can further enhance its potency for the treatment of breast cancer and potentially other cancer types.

Rhoifolin loaded in PLGA nanoparticles alleviates oxidative stress and inflammation in vitro and in vivo.

Rhoifolin (ROF) is a bioactive plant flavonoid with potent antioxidant and anti-inflammatory activity. However, no delivery system has yet been developed for ROF to overcome its biopharmaceutical limitations. The purpose of this study was to design a ROF-loaded polymeric nanocarrier as a potential anti-inflammatory nanomedicine. ROF was isolated from Jordanian Teucrium polium L. and entrapped into poly(lactide-co-glycolide) nanoparticles (PLGA NPs), followed by tannic acid-mediated surface modification with poly(ethylene glycol) (PEG). The optimal ROF NPs were highly monodisperse with an average diameter of 204 nm, a zeta potential of -28 mV, an entrapment efficiency of 45%, and drug loading of 9% w/w. The NPs exhibited excellent colloidal stability during storage and in the presence of serum and achieved sustained drug release for up to 96 h at physiologic (7.4) and acidic pH (5.0). In vitro cell-free antioxidant assays confirmed the potent radical scavenging activity of free ROF and ROF NPs. Moreover, ROF NPs were superior to free ROF in relieving oxidative stress in stimulated RAW 264.7 murine macrophages, which was attributed to enhanced cellular uptake of the NPs as confirmed by confocal microscopy and fluorimetry. In vivo anti-inflammatory activity was evaluated in a formalin-induced rat paw edema model. The results showed that ROF NPs were superior to free ROF in mitigating the histopathological changes in the inflamed paw tissues. Moreover, the NPs were equally potent to free ROF and the nonsteroidal anti-inflammatory drug diclofenac in terms of inhibiting the increase in paw thickness, normalizing nitric oxide levels, and modulating the gene expression of pro-inflammatory cytokines in the inflamed paw tissues. Our findings present a promising nanocarrier platform that can enhance the solubility and control the release of ROF, which will facilitate its administration in the treatment of inflammatory diseases.