Zahra Karami

Methotrexate (MTX), a frequently used chemotherapeutic agent, has limited water solubility, leading to rapid clearance even in local injections. In the present study, we developed folic acid-conjugated BSA-stabilized selenium-ZIF-8 core/shell nanoparticles for targeted delivery of MTX to combat breast cancer. FT-IR, XRD, SEM, TEM, and elemental mapping analysis confirmed the successful formation of FA-BSA@MTX@Se@ZIF-8. The developed nano-DDS had a mean diameter, polydispersity index, and zeta potential of 254.8 nm, 0.17, and − 16.5 mV, respectively. The release behavior of MTX from the nanocarriers was pH-dependent, where the cumulative release percentage at pH 5.4 was higher than at pH 7.4. BSA significantly improved the blood compatibility of nanoparticles so that after modifying their surface with BSA, the percentage of hemolysis decreased from 12.67 to 5.12%. The loading of methotrexate in BSA@Se@ZIF-8 nanoparticles reduced its IC₅₀ on 4T1 cells from 40.29 µg/mL to 16.54 µg/mL, and by conjugating folic acid on the surface, this value even decreased to 12.27 µg/mL. In vivo evaluation of the inhibitory effect in tumor-bearing mice showed that FA-BSA@MTX@Se@ZIF-8 caused a 2.8-fold reduction in tumor volume compared to the free MTX, which is due to the anticancer effect of selenium nanoparticles, the pH sensitivity of ZIF-8, and the presence of folic acid on the surface as a targeting agent. More importantly, histological studies and animal body weight monitoring confirmed that developed nano-DDS does not have significant organ toxicity. Taking together, the incorporation of chemotherapeutics in folic acid-conjugated BSA-stabilized selenium-ZIF-8 nanoparticles may hold a significant impact in the field of future tumor management. Graphical Abstract

Quercetin (Qc) possesses anti-cancer properties, such as cell signaling, growth suppression, pro-apoptotic, anti-proliferative, and antioxidant effects. In this study, we developed an alginate-modified ZIF-8 (Alg@ZIF-8) to enhance the anti-tumor efficacy of Qc. The developed alginate-modified quercetin-loaded ZIF-8 (Alg@Qc@ZIF-8) was characterized using scanning electron microscope (SEM), dynamic light scattering (DLS), fourier transform infrared spectroscopy Thermogravimetric analysis, Brunauer–Emmett–Teller, and x-ray diffraction. The drug release pattern was evaluated at pH 5.4 and 7.4. The cytotoxicity of nanoparticles was assessed on the 4T1 cell line. Finally, the anti-tumor activity of Alg@Qc@ZIF-8 was evaluated in 4T1 tumor-bearing mice. SEM showed that the nanoparticles were spherical with a diameter of mainly below 50 nm. The DLS showed that the developed nanoparticles’ hydrodynamic diameter, zeta potential, and polydispersity index were 154.9 ± 7.25 nm, −23.8 ± 5.33 mV, and 0.381 ± 0.09, respectively. The drug loading capacity was 10.40 ± 0.02%. Alg@Qc@ZIF-8 exhibited pH sensitivity, releasing more Qc at pH 5.4 (about 3.62 times) than at pH 7.4 after 24 h. Furthermore, the IC₅₀ value of Alg@Qc@ZIF-8 on the 4T1 cell line was 2.16 times lower than net Qc. Importantly, in tumor-bearing mice, Alg@Qc@ZIF-8 demonstrated enhanced inhibitory effects on tumor growth and lung metastasis compared to net Qc. Considering the in vitro and in vivo outcomes, Alg@Qc@ZIF-8 might hold great potential for effective breast cancer management.

Wide availability and easy accessibility of acetaminophen oral dosage forms increase the risk of intentional poisoning or unintentional organ toxicity, leading to a wide range of liver failure, nephrotoxicity, and neurotoxicity. In this study, an attempt was made to improve oral bioavailability and reduce the toxicity of acetaminophen using nanosuspension technology. The acetaminophen nanosuspensions (APAP-NSs) were prepared by a nano-precipitation method using polyvinyl alcohol and hydroxypropylmethylcellulose as stabilizers. The mean diameter of APAP-NSs was 124 +/- 3.8 nm. The dissolution profile of APAP-NSs was significantly point-to-point higher than the coarse drug in simulated gastrointestinal fluids. The in vivo study revealed 1.6- and 2.8-fold increases in the AUC(0-inf) and C-max of the drug, respectively, in APAP-NSs-receiving animals compared to the control group. Moreover, no deaths and no abnormalities in clinical signs, body weights, and necropsy findings were detected in the dose groups up to 100 mg/kg of the 28-day repeated oral dose toxicity study in mice.

The aim of the present study was to develop modified nanoemulsions to improve the oral bioavailability and pharmacokinetics of a poor water‐soluble drug, repaglinide (RPG). The repaglinide‐loaded nanoemulsions (RPG‐NEs) were prepared from olive oil as internal phase, span 80, tween 80, and poloxamer 188 as emulsifiers, using homogenization technique. The mean droplet size, zeta potential, and entrapment efficiency of RPG‐NEs were 86.5 ± 3.4 nm, −33.8 ± 2.1 mV, and 96.3 ± 2.3%, respectively. The chitosan‐coated RPG‐NEs (Cs‐RPG‐NEs) showed an average droplet size of 149.3 ± 3.9 nm and a positive zeta‐potential of +31.5 ± 2.8 mV. Drug release profile of RPG‐NEs was significantly higher than free drug in the simulated gastrointestinal fluids (p < .005). The in vivo study revealed 3.51‐ and 1.78‐fold increase in the AUC_0‐12h and C_max of the drug, respectively, in RPG‐NEs‐receiving animals in comparison to the free drug. The pharmacokinetic analysis confirmed that Cs‐RPG‐NEs were more efficient than uncoated ones for the oral delivery of RPG. Cs‐RPG‐NEs showed a longer t_1/2 and higher AUC_0‐∞ compared to control group. The relative bioavailability of Cs‐RPG‐NEs was higher than that of uncoated RPG‐NEs and free drug. Collectively, these findings suggest that chitosan‐coated nanoemulsions are promising carrier for improving the oral bioavailability of RPG.

Objective: Indinavir (IDV), an antiretroviral protease inhibitor used in treatment of HIV infection, has limited entry into brain due to efflux by the P-glycoprotein presented in blood–brain barrier. The aim of present study was to develop lactoferrin-treated nanoemulsion containing indinavir (Lf-IDV-NEs) for delivery to brain. Methods: Indinavir-loaded nanoemulsions (IDV-NEs) were prepared by high-speed homogenization method, and then lactoferrin was coupled to IDV-NEs by water soluble EDC method. Results: The hydrodynamic diameters, polydispersity index, and zeta potential of IDV-NEs were 112 ± 3.5 nm, 0.20 ± 0.02, and -33.2 ± 2.6 mV, respectively. From in vivo studies in animal model of rats, the AUC0-4h of brain concentration-time profile of IDV-NEs and Lf-IDV-NEs were 1.6 and 4.1 times higher than free drug, respectively. The brain uptake clearance of IDV-NEs and Lf-IDV-NEs were, interestingly, 393- and 420-times higher than the free drug. Conclusions: It can be concluded that applying both lactoferrin-treated and non-treated nanoemulsions clearly leads to significant brain penetration enhancement of indinavir, an effect which is more pronounced in the case of Lf-IDV-NEs with the higher drug residence time in brain.