Introduction

Breast cancer (BC) is the most common malignancy in women globally. Significant progress has been made in developing structural nanoparticles (NPs) and formulations for targeted smart drug delivery (SDD) of pharmaceuticals, improving the precision of tumor cell targeting in therapy.

Significance

Magnetic hyperthermia (MHT) treatment using magneto-liposomes (MLs) has emerged as a promising adjuvant cancer therapy.

Methods

CoFe₂O₄ magnetic NPs (MNPs) were conjugated with nanoliposomes to form MLs, and the anticancer drug quercetin (Que) was loaded into MLs, forming Que-MLs composites for antitumor approach. The aim was to prepare Que-MLs for DD systems (DDS) under an alternating magnetic field (AMF), termed chemotherapy/hyperthermia (chemo-HT) techniques. The encapsulation efficiency (EE), drug loading capacity (DL), and drug release (DR) of Que and Que-MLs were evaluated.

Results

The results confirmed successful Que-loading on the surface of MLs, with an average diameter of 38 nm and efficient encapsulation into MLs (69%). In vitro, experimental results on MCF-7 breast cells using MHT showed high cytotoxic effects of novel Que-MLs on MCF-7 cells. Various analyses, including cytotoxicity, apoptosis, cell migration, western blotting, fluorescence imaging, and cell membrane internalization, were conducted. The Acridine Orange-ethidium bromide double fluorescence test identified 35% early and 55% late apoptosis resulting from Que-MLs under the chemo-HT group. TEM results indicated MCF-7 cell membrane internalization and digestion of Que-MLs, suggesting the presence of early endosome-like vesicles on the cytoplasmic periphery.

Conclusions

Que-MLs exhibited multi-modal chemo-HT effects, displaying high toxicity against MCF-7 BC cells and showing promise as a potent cytotoxic agent for BC chemotherapy.

Introduction: Cancers are regarded as hazardous due to their high worldwide death rate, with breast cancer (BC), which affects practically all cancer patients globally, playing a significant role in this statistic. The therapeutic approach for BC has not advanced using standard techniques, such as specialized naringin (NG) chemotherapy. Instead, a novel strategy has been utilized to enhance smart drug delivery (SDD) to tumors.

Significance: Herein, we established NG-loaded zinc metal-organic framework-5 (NG-MOF-5) coated with liponiosomes (LNs) to manufacture NG-MOF-5@LNs nanoparticles (NPs) for antibacterial and cancer treatment.

Methods: MOF-5, NG, and NG-MOF-5@LNs were evaluated with XRD, thermogravimetric analysis (TGA), FTIR, SEM, TEM, PDI, ZP, encapsulation efficiency (EE), loading efficiency (LE), and drug release (DR) kinetics. We examined the antibacterial activity involving minimum inhibitory concentration (MIC) and zone of inhibition by NG, MOF-5, and NG-MOF-5@LNs. The cell viability, necrosis, and total apoptosis (late and early) were evaluated for anti-cancer activity against MCF-7 BC cells.

Results: TEM results demonstrated that NG-MOF-5@LNs formed monodispersed spherical-like particles with a size of 122.5 nm, PDI of 0.139, and ZP of +21 mV. The anti-microbial activity results indicated that NG-MOF-5@LNs exhibited potent antibacterial effects, as evidenced by inhibition zones and MIC values. The Higuchi model indicates an excellent fit (R² = 0.9988). The MTT assay revealed anti-tumor activity against MCF-7 BC cells, with IC₅₀ of 21 µg/mL for NG-MOF-5@LNs and demonstrating a total apoptosis effect of 68.2% on MCF-7 cells.

Conclusion: NG-MOF-5@LNs is anticipated to show as an effective antimicrobial and novel long-term-release antitumor agent and might be more suitable for MCF-7 cell therapy.

Background:  Obesity has become a prevalent issue worldwide, leading to various complications such as hyperlipidemia, diabetes, and cardiovascular problems. Statins, as FDA approved anti-hyperlipidemic drugs still pose some concerns upon their administration. Recently, researchers have looked for natural products as an alternative to manage hyperlipidemia and obesity. Aim: This work aimed to study the hypolipidemic effect of Lepidium sativum garden cress (GC) from differen preparations; orally administered seeds, and hydrogel, in comparison to atorvastatin. Methods:  GC hydrogel was prepared from the GC aqueous extract and pharmaceutically evaluated for it pH, spreadability, seeds content, homogeneity, rheology, and in vitro release. The rat’s body weight, bloo glucose levels, total lipid profile, and liver biomarkers were evaluated on obese rats for one month. In addition, the histopathology study was also performed. Results: GC hydrogel had acceptable pharmaceutical properties and showed a sustained release performance over 24h. Oral and topical GC significantly reduced the lipid profiles, blood sugar and AT, AST level than the negative control group and comparable to atorvastatin. It was found that oral GC showed significant effect on the percentage decrease in the rat’s body weight than the applied hydrogel. Histopathology study revealed a better outcome in the histological structure of pancreas and liver compared with rats feed on high fat diet post-treatment for one month. Conclusion:  GC orally administered, or topically applied hydrogel could be a promising, safe alternative formulation to atorvastatin in managing hyperlipidemia and normalizing body weight of obese rats

The low and erratic oral absorption of sulpiride (SUL) a dopaminergic receptor antagonist, and its P-glycoprotein efflux in the gastrointestinal tract restricted its oral route for central nervous system disorders. An intranasal formulation was formulated based on nanostructured lipid carrier to tackle these obstacles and deliver SUL directly to the brain. Sulipride-loaded nanostructured lipid carrier (SUL-NLC) was prepared using compritolVR 888 ATO and different types of liquid lipids and emulsifiers. SUL-NLCs were characterized for their particle size, charge, and encapsulation efficiency. Morphology and compatibility with other NLC excipients were also studied. Moreover, SUL in vitro release, nanodispersion stability, in vivo performance and SUL pharmacokinetics were investigated. Results delineates that SUL-NLC have a particle size ranging from 366.2 ± 62.1 to 640.4 ± 50.2 nm and encapsulation efficiency of 75.5 ± 1.5%. SUL showed a sustained release pattern over 24 h and maintained its physical stability for three months. Intranasal SUL-NLC showed a significantly (p < 0.01) higher SUL brain concentration than that found in plasma after oral administration of commercial SUL product with 4.47-fold increase in the relative bioavailability. SUL-NLCs as a nose to brain approach is a promising formulation for enhancing the SUL bioavailability and efficient management of neurological disorders.

Mutant EGFR/BRAF pathways are thought to be crucial targets for the development
of anticancer drugs since they are over-activated in several malignancies. We present here the
development of a novel series of 5-chloro-indole-2-carboxylate 3a–e, 4a–c and pyrrolo[3,4-b]indol-3-
ones 5a–c derivatives as potent inhibitors of mutant EGFR/BRAF pathways with antiproliferative
activity. The cell viability assay results of 3a–e, 4a–c, and 5a–c revealed that none of the compounds
tested were cytotoxic, and that the majority of those tested at 50 M had cell viability levels greater
than 87%. Compounds 3a–e, 4a–c, and 5a–c had significant antiproliferative activity with GI50 values
ranging from 29 nM to 78 nM, with 3a–e outperforming 4a–c and 5a–c in their inhibitory actions
against the tested cancer cell lines. Compounds 3a–e were tested for EGFR inhibition, with IC50
values ranging from 68 nM to 89 nM. The most potent derivative was found to be the m-piperidinyl
derivative 3e (R = m-piperidin-1-yl), with an IC50 value of 68 nM, which was 1.2-fold more potent
than erlotinib (IC50 = 80 nM). Interestingly, all the tested compounds 3a–e had higher anti-BRAFV600E
activity than the reference erlotinib but were less potent than vemurafenib, with compound 3e having
the most potent activity. Moreover, compounds 3b and 3e showed an 8-fold selectivity index toward
EGFRT790M protein over wild-type. Additionally, molecular docking of 3a and 3b against BRAFV600E
and EGFRT790M enzymes revealed high binding affinity and active site interactions compared to the
co-crystalized ligands. The pharmacokinetics properties (ADME) of 3a–e revealed safety and good
pharmacokinetic profile

Thiazole and thiazolidinone recur in a wide range of biologically active compounds
that reach different targets within the context of tumors and represent a promising starting point
to access potential candidates for treating metastatic cancer. Therefore, searching for new lead
compounds that show the highest anticancer potency with the fewest adverse effects is a major
drug-discovery challenge. Because the thiazole ring is present in dasatinib, which is currently used in
anticancer therapy, it is important to highlight the ring. In this study, cycloalkylidenehydrazinecarbothioamides
(cyclopentyl, cyclohexyl, cyclooctyl, dihydronapthalenylidene, flurine-9-ylidene, and
indolinonyl) reacted with 2-bromoacetophenone and diethylacetylenedicarboxylate to yield thiazole
and 4-thiazolidinone derivatives. The structure of the products was confirmed by using infrared (IR)
spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and single-crystal
X-ray analyses. The antiproliferative activity of the newly synthesized compounds was evaluated.
The most effective inhibitory compounds were further tested in vitro against both epidermal growth
factor receptor (EGFR) and B-Raf proto-oncogene, serine/threonine kinase (BRAFV600E) targets. Additionally,
molecular docking analysis examined how these molecules bind to the active sites of EGFR
and BRAFV600E

everal studies have indicated the potential therapeutic outcomes of combining selective COX-2 inhibitors with
tubulin-targeting anticancer agents. In the current study, a novel series of thiazolidin-4-one-based derivatives
(7a–q) was designed by merging the pharmacophoric features of some COXs inhibitors and tubulin polymerization
inhibitors. Compounds 7a–q were synthesized and evaluated for their cytotoxic activity against MCF7,
HT29, and A2780 cancer cell lines (IC50 = 0.02–17.02 μM). The cytotoxicity of 7a–q was also assessed against
normal MRC5 cells (IC50 = 0.47–13.46 μM). Compounds 7c, 7i, and 7j, the most active in the MTT assay,
significantly reduced the number of HT29 colonies compared to the control. Compounds 7c, 7i, and 7j also
induced significant decreases in the tumor volumes and masses in Ehrlich solid carcinoma-bearing mice
compared to the control. The three compounds also exhibited significant anti-HT29 migration activity in the
wound-healing assay. They have also induced cell cycle arrest in HT29 cells at the S and G2/M phases. In
addition, they induced significant increases in both early and late apoptotic events in HT29 cells compared to the
control, where 7j showed the highest effect. On the other hand, compound 7j (1 μM) displayed weak inhibitory
activity against tubulin polymerization compared to colchicine (3 μM). On the other hand, compounds 7a–q
inhibited the activity of COX-2 (IC50 = 0.42–29.11 μM) compared to celecoxib (IC50 = 0.86 μM). In addition, 7c,
7i, and 7j showed moderate inhibition of inflammation in rats compared to indomethacin, with better GIT safety
profiles. Molecular docking analysis revealed that 7c, 7i, and 7j have higher binding free energies towards COX-2
than COX-1. These above results suggested that 7j could serve as a potential anticancer drug candidate

The reaction of 4-azido-quinolin-2(1H)-ones 1a–e with the active methylene compounds
pentane-2,4-dione (2a), 1,3-diphenylpropane-1,3-dione (2b), and K2CO3 was investigated in this
study. This approach afforded 4-(1,2,3-triazol-1-yl)quinolin-2(1H)-ones 3a–j in high yields and
purity. All newly synthesized products’ structures were identified. Compounds 3a–j were tested
for antiproliferative activity against a panel of four cancer cell lines. In comparison to the reference
erlotinib (GI50 = 33), compounds 3f–j were the most potent derivatives, with GI50 values ranging
from 22 nM to 31 nM. The most effective antiproliferative derivatives, 3f–j, were subsequently
investigated as possible multi-target inhibitors of EGFR, BRAFV600E, and EGFRT790M. Compound 3h
was the most potent inhibitor of the studied molecular targets, with IC50 values of 57 nM, 68 nM, and
9.70 nM, respectively. The apoptotic assay results demonstrated that compounds 3g and 3h function
as caspase-3, 8, and Bax activators as well as down-regulators of the antiapoptotic Bcl2, and hence can
be classified as apoptotic inducers. Finally, compounds 3g and 3h displayed promising antioxidant
activity at 10 M, with DPPH radical scavenging of 70.6% and 73.5%, respectively, compared to
Trolox (77.6%)

A new series of indole-2-carboxamides 5a-g, 6a-f and pyrido[3,4-b]indol-1-ones 7a and 7b have been developed
as new antiproliferative agents that target both wild and mutant type EGFR. The antiproliferative effect of
the new compounds was studied. 5c, 5d, 5f, 5g, 6e, and 6f have the highest antiproliferative activity with GI50
values ranging from 29 nM to 47 nM in comparison to the reference erlotinib (GI50 ¼ 33nM). Compounds 5d,
5f, and 5g inhibited EGFRWT with IC50 values ranging from 68 to 85 nM while the GI50 of erlotinib is 80 nM.
Moreover, compounds 5f and 5g had the most potent inhibitory activity against EGFRT790M with IC50 values of
9.5± 2 and 11.9 ±3nM, respectively, being equivalent to the reference osimertinib (IC50 ¼ 8±2nM).
Compounds 5f and 5g demonstrated excellent caspase-3 protein overexpression levels of 560.2±5.0 and
542.5±5.0 pg/mL, respectively, being more active than the reference staurosporine (503.2±4.0 pg/mL). they
also increase the level of caspase 8, and Bax while decreasing the levels of anti-apoptotic Bcl2 protein.
Computational docking studies supported the enzyme inhibition results and provided favourable dual binding
modes for both compounds 5f and 5g within EGFRWT and EGFRT790M active sites. Finally, in silico
ADME/pharmacokinetic studies predict good safety and pharmacokinetic profile of the most active compounds

Some new Bis-pyrazoline hybrids 8–17 with dual EGFR and BRAFV600E inhibitors have
been developed. The target compounds were synthesized and tested in vitro against four cancer
cell lines. Compounds 12, 15, and 17 demonstrated strong antiproliferative activity with GI50 values
of 1.05 M, 1.50 M, and 1.20 M, respectively. Hybrids showed dual inhibition of EGFR and
BRAFV600E. Compounds 12, 15, and 17 inhibited EGFR-like erlotinib and exhibited promising
anticancer activity. Compound 12 is the most potent inhibitor of cancer cell proliferation and
BRAFV600E. Compounds 12 and 17 induced apoptosis by increasing caspase 3, 8, and Bax levels, and
resulted in the downregulation of the antiapoptotic Bcl2. The molecular docking studies verified that
compounds 12, 15, and 17 have the potential to be dual EGFR/BRAFV600E inhibitors. Additionally, in
silico ADMET prediction revealed that most synthesized bis-pyrazoline hybrids have low toxicity and
adverse effects. DFT studies for the two most active compounds, 12 and 15, were also carried out. The
values of the HOMO and LUMO energies, as well as softness and hardness, were computationally
investigated using the DFT method. These findings agreed well with those of the in vitro research
and molecular docking study