Farshid Hassanzadeh

Anti-tumor agent, docetaxel (DTX), was incorporated into novel pre-synthesized pH-triggered folate-targeted polymeric micelles to overcome insufficient drug accumulation at the tumor site and to reduce side effects in healthy tissues. Tumor growth inhibition rate (87.8%), elimination half-life (7.15 h), and tumor targeting efficiency (74.3%) for the targeted micellar formulation were significantly improved compared to those of free DTX (52.14%, 4.98 h, and 52.92% respectively). Overall, the findings of the current study showed that folate-targeted micelle is a potential targeting drug delivery system improving the efficacy of anticancer drugs through selective targeting of tumor tissues.

Summary This study aimed to prepare SLC7A5 transporters targeted liposomes of Ribociclib (RB) by stear(o)yl conjugation of Phe, Asp, Glu amino acids to liposomes as targeting moieties. The liposomes were optimized for their formulations. Cell analysis on two cell lines of MCF-7 and NIH-3T3 were done including; cell viability test by MTT assay, cellular uptake, and cell cycle arrest by flow cytometry. The optimal liposomes showed the particle size of 123.6 ± 1.3 nm, drug loading efficiency and release efficiency of 83.87% ± 1.33% and 60.55% ± 0.46%, respectively. The RB loaded liposomes showed no hemolysis activity. Targeted liposomes increased cytotoxicity on MCF-7 cells more significantly than NIH-3T3 cells. Cell flow cytometry indicated that targeted liposomes uptake was superior to plain (non-targted) liposomes and free drug. Free drug and RB-loaded liposomes interrupted cell cycle in G1. However, amino acid-targeted liposomes arrested cells more than the free drug at this stage. Targeted liposomes reduced cell cycle with more interruption in the G2/M phase compared to the negative control. Graphical abstract

In this study, by combining azlactone–benzoxazinone chemistry, we synthesized new hybrid compounds and evaluated the in vitro cytotoxicity on the breast cancer cell line. The desired compounds were synthesized using green and straightforward chemical reactions on azlactone and benzoxazinone structures through simple ring closure and nucleophilic ring-opening reactions. Preliminary in vitro cytotoxic results on the MCF-7 breast cancer cell line showed that the synthesized compounds have excellent anticancer activity with interestingly low inhibitory concentrations (IC50s in the range of 8–20 mM). Fortunately, our structures simultaneously had low toxicity on the normal HUVEC cell line. Finally, molecular docking studies were performed on the EGFR enzyme as one of the active signaling pathways in cancer cells for the best cytotoxic candidates. In this regard, the alignment of the docking and cytotoxicity results was interesting. In conclusion, these potential cytotoxic compounds could be considered in further studies.

In this work, new derivatives of biphenyl pyrazole-benzofuran hybrids were designed, synthesized and evaluated in vitro through enzymatic assay for inhibitory effect against α-glucosidase activity. Newly identified inhibitors were found to be four to eighteen folds more active with IC₅₀ values in the range of 40.6 ± 0.2–164.3 ± 1.8 µM, as compared to the standard drug acarbose (IC₅₀ = 750.0 ± 10.0 μM). Limited Structure-activity relationship was established. A kinetic binding study indicated that most active compound 8e acted as the competitive inhibitors of α-glucosidase with K_i = 38 μM. Molecular docking has also been performed to find the interaction modes responsible for the desired inhibitory activity. As expected, all pharmacophoric features, used in the design of the hybrid, are involved in the interaction with the active site of the enzyme. In addition, molecular dynamic simulations showed compound 8e oriented vertically into the active site from mouth to the bottom and stabilized the enzyme domains by interacting with the interface of domain A and domain B and the back side of the active site while acarbose formed non-binding interaction with the residue belong to the domain A of the enzyme.

Boron neutron capture therapy (BNCT) is one of the best treatment modalities for glioblastoma multiform that could selectively kill the tumor cells. To be successful in BNCT, it is crucial to have enough ¹⁰B in the tumor. l-boron phenylalanine (l-BPA) targeted thermo-responsive core–shell nanoparticles (NPs) of chitosan-poly(N-isopropylacrylamide) (PNIPAAm) were our idea for endocytosis via sialic acid receptors, and selective delivery of ¹⁰B to glial cells. Methotrexate (MTX) was chosen as a model drug for evaluating the efficacy of NPs in tumor cells, and BPA was selected for BNCT purposes. The polymeric conjugates were synthesized and the chemical structures were approved by spectroscopic methods (FTIR, ¹H NMR, and ¹¹B NMR). Cargos were loaded efficiently (>95%) in the prepared NPs, and the release profile of MTX and BPA was studied around the lower critical solution temperature (LCST; about 39 °C). The loaded drugs were released quantitatively at the LCST, while almost no drug was released at 37 °C. The prepared NPs did not show considerable hemolysis ratio (50 (30.78 µg/mL) than the free MTX (37.03 µg/mL) in MTT assay, and targeted NPs had the lowest IC₅₀s in U87MG cell lines (27.35 µg/mL). Targeted BPA@CSSU-PNI NPs were uptaken better than the non-targeted ones by U87MG cells, and CR-39 assay showed the boron content efficiency for further applications in BNCT. This study's results introduce novel targeted thermo-responsive NPs for treating glioblastoma using BNCT. Graphical Abstract

Background and purpose: Alzheimer’s disease is considered one of the lead causes of elderly death around the world. A significant decrease in acetylcholine level in the brain is common in most patients with Alzheimer’s disease, therefore acetylcholinesterase (AChE) inhibitors such as donepezil and rivastigmine are widely used for patients with limited therapeutic results and major side effects. Experimental approach: A series of isoindoline-1,3-dione -N-benzyl pyridinium hybrids were designed, synthesized and evaluated as anti-Alzheimer agents with cholinesterase inhibitory activities. The structure of the compounds were confirmed by various methods of analysis such as HNMR, CNMR, and FT-IR. Molecular modeling studies were also performed to identify the possible interactions between neprilysin and synthesized compounds. Findings/Results: The biological screening results indicated that all synthesized compounds displayed potent inhibitory activity with IC₅₀ values ranging from 2.1 to 7.4 μM. Among synthesized compounds, para-fluoro substituted compounds 7a and 7f exhibited the highest inhibitory potency against AChE (IC₅₀ = 2.1 μM). Molecular modeling studies indicated that the most potent compounds were able to interact with both catalytic and peripheral active sites of the enzyme. Also, some of the most potent compounds (7a, 7c, and 7f) demonstrated a neuroprotective effect against H₂O₂-induced cell death in PC12 neurons. Conclusion and implications: The synthesized compounds demonstrated moderate to good AChE inhibitory effect with results higher than rivastigmine.

Nanotechnology has revolutionized drug delivery in cancer treatment. In this study, novel efficient pH-responsive boron phenylalanine (BPA) targeted nanoparticles (NPs) based on ionic liquid modified chitosan have been introduced for selective mitoxantrone (MTO) delivery to the U87MG glioma cells. Urocanic acid (UA) and imidazolium (Im) based ionic liquids were used for structural modification simultaneously. The NPs were prepared by ionic gelation and fully characterized; the pH-responding and swelling index of NPs were studied carefully. The drug release was studied at a pH of 5.5 in comparison to the neutral state. Also, the cytotoxicity of loaded NPs was evaluated on U87MG glial cells, and cellular uptake was studied. The NPs were smaller than 250 nm, with a spherical pattern and acceptable uniformity with a zeta potential around +20 mV. The loading efficacy was about 85%, and most of the loaded MTO released at a pH of 5.5 after 48 h with a swelling-controlled mechanism. The NPs showed a relatively lower IC₅₀ than the free MTO, and the BPA-targeted NPs have lower IC₅₀ and better cellular uptake than non-targeted NPs in U87MG cells. More studies on this promising formula are on the way, and the results will be published soon. Graphical Abstract

In this work, new derivatives of biphenyl pyrazole-benzofuran hybrids designed, synthesized and evaluated in vitro through enzymatic assay for inhibitory effect against α-glucosidase activity. Newly identified inhibitors were found to be four to eighteen folds more active with IC₅₀ values in the range of 40.6 ± 0.2–164.3 ± 1.8 µM, as compared to the standard drug acarbose (IC₅₀ = 750.0 ± 10.0 µM). Limited Structure-activity relationship was established. A kinetic binding study indicated that most active compound 8e acted as the competitive inhibitors of α-glucosidase with Ki = 38 µM. Molecular docking has also been performed to find the interaction modes responsible for the desired inhibitory activity. As expected, all pharmacophoric features used in the design of the hybrid, are involved in the interaction with the active site of the enzyme. In addition, molecular dynamic simulations showed compound 8e oriented vertically into the active site from mouth to the bottom and stabilized the enzyme domains by interacting with the interface of domain A and domain B and the back side of the active site while acarbose formed non-binding interaction with the residue belong to the domain A of the enzyme.