Synthesis, antileishmanial, antimalarial evaluation and molecular docking study of some hydrazine-coupled pyrazole derivatives.

Pyrazole-bearing compounds are known for their diverse pharmacological effects including potent antileishmanial and antimalarial activities. Herein, some hydrazine-coupled pyrazoles were successfully synthesized and their structures were verified by employing elemental microanalysis, FTIR, and 1H NMR techniques. The in vitro antileishmanial and in vivo antimalarial activities of the synthesized pyrazole derivatives (9-15) were evaluated against Leishmania aethiopica clinical isolate and Plasmodium berghei infected mice, respectively. The result revealed that compound 13 displayed superior antipromastigote activity (IC50 = 0.018) that was 174- and 2.6-fold more active than the standard drugs miltefosine (IC50 = 3.130) and amphotericin B deoxycholate (IC50 = 0.047). The molecular docking study conducted on Lm-PTR1, complexed with Trimethoprim was acquired from the Protein Data Bank (PDB ID:2bfm), justified the better antileishmanial activity of compound 13. Furthermore, the target compounds 14 and 15 elicited better inhibition effects against Plasmodium berghei with 70.2% and 90.4% suppression, respectively. In conclusion, the hydrazine-coupled pyrazole derivatives may be considered potential pharmacophores for the preparation of safe and effective antileishmanial and antimalarial agents.

Hydrogen-Bonding Interactions from Nucleobase-Decorated Supramolecular Polymer: Synthesis, Self-Assembly and Biomedical Applications.

The fabrication of supramolecular materials for biomedical applications such as drug delivery, bioimaging, wound-dressing, adhesion materials, photodynamic/photothermal therapy, infection control (as antibacterial), etc. has grown tremendously, due to their unique properties, especially the formation of hydrogen bonding. Nevertheless, void space in the integration process, lack of feasibility in the construction of supramolecular materials of natural origin in living biological systems, potential toxicity, the need for complex synthesis protocols, and costly production process limits the actual application of nanomaterials for advanced biomedical applications. On the other hand, hydrogen bonding from nucleobases is one of the strategies that shed light on the blurred deployment of nanomaterials in medical applications, given the increasing reports of supramolecular polymers that promote advanced technologies. Herein, we review the extensive body of literature about supramolecular functional biomaterials based on nucleobase hydrogen bonding pertinent to different biomedical applications. It focuses on the fundamental understanding about the synthesis, nucleobase-decorated supramolecular architecture, and novel properties with special emphasis on the recent developments in the assembly of nanostructures via hydrogen-bonding interactions of nucleobase. Moreover, the challenges, plausible solutions, and prospects of the so-called hydrogen bonding interaction from nucleobase for the fabrication of functional biomaterials are outlined.

Phytochemical constituents, antioxidant and antibacterial activities of Plectocephalus varians (A. Rich.) C. Jeffrey ex Cufod root extracts.

Plants have been used to treat diverse types of diseases in different cultural groups around the globe. In this regard, the root of Plectocephalus varians (P. varians) is claimed to have a beneficiary effect in treating cancer and hemorrhoids in Ethiopia. Hence, this study aimed at the phytochemical investigation, antioxidant, and antibacterial activities of n-hexane, acetone, and methanolic extracts of P. varians root. The different crude extracts of P. varians were obtained through maceration technique. The total phenolic content (TPC) and total flavonoid contents (TFC) of the extracts were estimated using Folin-Ciocalteu Reagent (FCR) and aluminum chloride colorimetric assays, respectively. The antioxidant activities of the extracts were determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging and ferric reducing antioxidant power (FRAP) assays. The antibacterial activities of the extracts were assessed by using disc diffusion method. The results echoed the presence of alkaloids, saponins, flavonoids, steroids, phenols, tannins, anthraquinones, terpenoids, polyphenols, and glycosides in the root of P. varians. The methanolic root extract (MRE) had the highest TPC (107.18 mg GAE/g) and TFC (120.194 mg QE/g) followed by acetone root extract (ARE) (TPC = 98.68 mg GAE/g; TFC = 64.038 mg QE/g) and n-hexane root extract (HRE) (TPC = 12.39 mg GAE/g; TFC = 9.917 mg QE/g). The DPPH radical scavenging and FRAP assays demonstrated the antioxidant effects of HRE (IC50 = 681.75 ppm; EC50 = 60.65 ppm), ARE (IC50 = 165.73 ppm; EC50 = 51.67 ppm) and MRE (IC50 = 132.06 ppm; EC50 = 30.97 ppm) of P. varians. Furthermore, the root fractions elicited pronounced dose-dependent growth inhibition against Staphylococcus aureus, Streptococci pyogenes, Escherichia coli, and Klebsiella pneumoniae with mean zone of inhibition (MZI) ranging from 11 ± 0.38 to 20 ± 0.04 mm at 800 ppm. Overall, the present study provides ethnopharmacological evidence suggesting the medicinal importance of P. varians. The results also call for further bioassay-guided phytochemical screening and in vitro and/or in vivo bioactivity testing.

Plasmonic surface-enhanced Raman scattering nano-substrates for detection of anionic environmental contaminants: Current progress and future perspectives.

Surface-enhanced Raman scattering spectroscopy (SERS) is a powerful technique of vibrational spectroscopy based on the inelastic scattering of incident photons by molecular species. It has unique properties such as ultra-sensitivity, selectivity, non-destructivity, speed, and fingerprinting properties for analytical and sensing applications. This enables SERS to be widely used in real-world sample analysis and basic plasmonic mechanistic studies. However, the desirable properties of SERS are compromised by the high cost and low reproducibility of the signals. The development of multifunctional, stable and reusable nano-engineered SERS substrates is a viable solution to circumvent these drawbacks. Recently, plasmonic SERS active nano-substrates with various morphologies have attracted the attention of researchers due to promising properties such as the formation of dense hot spots, additional stability, tunable and controlled morphology, and surface functionalization. This comprehensive review focused on the current advances in the field of SERS active nanosubstrates suitable for the detection and quantification of anionic environmental pollutants. The common fabrication methods, including the techniques for morphological adjustments and surface modification, substrate categories, and the design of nanotechnologically fabricated plasmonic SERS substrates for anion detection are systematically presented. Here, the need for the design, synthesis, and functionalization of SERS nano-substrates for anions of great environmental importance is explained in detail. In addition, the broad categories of SERS nano-substrates, namely colloid-based SERS substrates and solid-support SERS substrates are discussed. Moreover, a brief discussion of SERS detection of certain anionic pollutants in the environment is presented. Finally, the prospects in the fabrication and commercialization of pilot-scale handheld SERS sensors and the construction of smart nanosubstrates integrated with novel amplifying materials for the detection of anions of environmental and health concern are proposed.

Synthesis, antimalarial, antileishmanial evaluation, and molecular docking study of some 3-aryl-2-styryl substituted-4(3H)-quinazolinone derivatives.

Quinazolinones are a diverse group of nitrogen-containing heterocyclic compounds with promising antimalarial and antileishmanial activities. Herein, some 3-aryl-2-styryl substituted-4(3H)-quinazolinones were synthesized via cyclization, condensation, and hydrolysis reactions. 1H NMR, FTIR and elemental microanalysis was used to verify the structures of the synthesized compounds. The in vivo antimalarial and in vitro antileishmanial activities of the target compounds were investigated using mice infected with Plasmodium berghi ANKA and Leishmania donovani strain, respectively. Among the test compounds, 8 and 10 showed better antimalarial activities with percent suppression of 70.01 and 74.18, respectively. In addition, (E)-2-(4-nitrostyryl)-3-phenylquinazolin-4(3H)-one (6) showed promising antileishmanial activity (IC50 = 0.0212 µg/mL). It is two and 150 times more active than the standard drugs amphotericin B deoxycholate (IC50 = 0.0460 µg/mL) and miltefosine (IC 50 = 3.1911 µg/mL), respectively. Its superior in vitro antileishmanial activity was supported by a molecular docking study conducted in the active site of Lm-PTR1. Overall, the synthesized 3-aryl-2-styryl substituted-4(3H)-quinazolinones showed promising antileishmanial and antimalarial activities and are desirable scaffolds for the synthesis of different antileishmanial and antimalarial agents.

Medicinal plants utilized in the management of epilepsy in Ethiopia: ethnobotany, pharmacology and phytochemistry.

Epilepsy is a common central nervous system (CNS) disorder that affects 50 million people worldwide. Patients with status epilepticus (SE) suffer from devastating comorbidities and a high incidence of mortalities. Antiepileptic drugs (AEDs) are the mainstream treatment options for the symptomatic relief of epilepsy. The incidence of refractory epilepsy and the dose-dependent neurotoxicity of AEDs such as fatigue, cognitive impairment, dizziness, attention-deficit behavior, and other side effects are the major bottlenecks in epilepsy treatment. In low- and middle-income countries (LMICs), epilepsy patients failed to adhere to the AEDs regimens and consider other options such as complementary and alternative medicines (CAMs) to relieve pain due to status epilepticus (SE). Plant-based CAMs are widely employed for the treatment of epilepsy across the globe including Ethiopia. The current review documented around 96 plant species (PS) that are often used for the treatment of epilepsy in Ethiopia. It also described the in vivo anticonvulsant activities and toxicity profiles of the antiepileptic medicinal plants (MPs). Moreover, the phytochemical constituents of MPs with profound anticonvulsant effects were also assessed. The result reiterated that a lot has to be done to show the association between herbal-based epilepsy treatment and in vivo pharmacological activities of MPs regarding their mechanism of action (MOA), toxicity profiles, and bioactive constituents so that they can advance into the clinics and serve as a treatment option for epilepsy.

pH/redox-responsive core cross-linked based prodrug micelle for enhancing micellar stability and controlling delivery of chemo drugs: An effective combination drug delivery platform for cancer therapy.

Core-crosslinking of micelles (CCMs) appears to be a favorable strategy to enhance micellar stability and sustained release of the loaded drug. In this study, the DOX-conjugated pH-sensitive polymeric prodrug Methoxy Poly (ethylene oxide)-b-Poly (Aspartate-Hydrazide) (mPEG-P [Asp-(Hyd-DOX)] was created using ring-opening polymerization. To further enhance the micellar system, 3,3'-diselanediyldipropanoic acid (DSeDPA) was applied to link the hydrophobic segment via click reaction to form pH/redox-responsive CCMs. Dual anti-cancer drugs, DOX as a pro-drug and SN-38 as a targeting drug, were used to enhance inhibition. DLS confirmed that the non-cross-linked micelle (NCMs) showed a higher (96.43 nm) particle size compared to the CCMs (72.63 nm). Due to micellar shrinkage after crosslinking, CCMs displayed SN-38 drug loading (7.32 %) and encapsulation efficiency (86.23 %). The mPEG-P(Asp-Hyd) copolymer's in vitro cytotoxicity on HeLa and HaCaT cell lines found that 84.52 % of the cells are alive, and zebrafish (Danio rerio) embryos and larvae are highly biocompatible. The DOX/SN-38@CCMs had a sustained discharge profile in vitro, unlike the DOX/SN-38@NCMs. In DOX/SN-38@CCMs, HeLa cells were inhibited 50.90 % more than HaCaT (14.25 %) at the maximum drug dose (10 µg/mL). The CCMs successfully targeted and supplied DOX/SN-38 in HeLa cells rather than HaCaT cells, based on cellular uptake of 2D cell culture. CCMs, unlike NCMs, inhibit the growth of spheroids for extended periods of time due to the prolonged release of the loaded drug. Overall, CCMs are good-looking for use as regulated delivery of DOX/SN-38 in cancer cells because of all of these appealing characteristics.

PAMAM Dendritic Nanoparticle-Incorporated Hydrogel to Enhance the Immunogenic Cell Death and Immune Response of Immunochemotherapy.

The efficiency of chemotherapy is frequently affected by its multidrug resistance, immune suppression, and severe side effects. Its combination with immunotherapy to reverse immune suppression and enhance immunogenic cell death (ICD) has emerged as a new strategy to overcome the aforementioned issues. Herein, we construct a pH-responsive PAMAM dendritic nanocarrier-incorporated hydrogel for the co-delivery of immunochemotherapeutic drugs. The stepwise conjugation of moieties and drug load was confirmed by various techniques. In vitro experimental results demonstrated that PAMAM dendritic nanoparticles loaded with a combination of drugs exhibited spherical nanosized particles, facilitated the sustained release of drugs, enhanced cellular uptake, mitigated cell viability, and induced apoptosis. The incorporation of PAB-DOX/IND nanoparticles into thermosensitive hydrogels also revealed the formation of a gel state at a physiological temperature and further a robust sustained release of drugs at the tumor microenvironment. Local injection of this formulation into HeLa cell-grafted mice significantly suppressed tumor growth, induced immunogenic cell death-associated cytokines, reduced cancer cell proliferation, and triggered a CD8+ T-cell-mediated immune response without obvious systemic toxicity, which indicates a synergistic ICD effect and reverse of immunosuppression. Hence, the localized delivery of immunochemotherapeutic drugs by a PAMAM dendritic nanoparticle-incorporated hydrogel could provide a promising strategy to enhance antitumor activity in cancer therapy.

Combination of ovalbumin-coated iron oxide nanoparticles and poly(amidoamine) dendrimer-cisplatin nanocomplex for enhanced anticancer efficacy.

Enhancement of drug efficacy is essential in cancer treatment. The immune stimulator ovalbumin (Ova)-coated citric acid (AC-)-stabilized iron oxide nanoparticles (AC-IO-Ova NPs) and enhanced permeability and retention (EPR)-based tumor targeted 4.5 generation poly(amidoamine) dendrimer(4.5GDP)-cisplatin (Cis-pt) nanocomplex (NC) (4.5GDP-Cis-pt NC) were used for enhanced anticancer efficiency. The formations of 4.5GDP-Cis-pt NC, AC-IO, and AC-IO-Ova NPs were examined via FTIR spectroscopy, X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy. The conjugation of Cis-pt with 4.5GDP was confirmed using carbon NMR spectroscopy. The tumor-specific 4.5GDP-Cis-pt NC provided 45%and 28% cumulative cisplatin release in 72 h at pH 6.5 and 7.4, respectively. A significant immune response with high TNF-α and IL-6 cytokine secretion was confirmed for the co-incubation of AC-IO-Ova with RAW 264.7 or HaCaT cells. AC-IO-Ova NPs were biocompatible with different cell lines, even at a high concentration (200 µg mL-1). However, AC-IO-Ova NPs mixed with 4.5GDP-Cis-pt NC (Cis-pt at 15 µg mL-1) significantly increased the cytotoxicity against the cancer cells in a dose-dependent manner with the increasing AC-IO-Ova NPs concentrations. The increased anticancer effects may be attributed to the generation of reactive oxygen species (ROS). Moreover, AC-IO-Ova NPs might assist the efficiency of anticancer cells, inducing an innate immune response via M1 macrophage polarization. We provide a novel synergistic chemoimmunotherapeutic strategy to enhance the anticancer efficacy of cisplatin via a chemotherapeutic agent 4.5GDP-Cis-pt NC and induce proinflammatory cytokines stimulating innate immunity through AC-IO-Ova NPs against tumors.

Recent developments in selenium-containing polymeric micelles: prospective stimuli, drug-release behaviors, and intrinsic anticancer activity.

Selenium is capable of forming a dynamic covalent bond with itself and other elements and can undergo metathesis and regeneration reactions under optimum conditions. Its dynamic nature endows selenium-containing polymers with striking sensitivity towards some environmental alterations. In the past decade, several selenium-containing polymers were synthesized and used for the preparation of oxidation-, reduction-, and radiation-responsive nanocarriers. Recently, thioredoxin reductase, sonication, and osmotic pressure triggered the cleavage of Se-Se bonds and swelling or disassembly of nanostructures. Moreover, some selenium-containing nanocarriers form oxidation products such as seleninic acids and acrylates with inherent anticancer activities. Thus, selenium-containing polymers hold promise for the fabrication of ultrasensitive and multifunctional nanocarriers of radiotherapeutic, chemotherapeutic, and immunotherapeutic significance. Herein, we discuss the most recent developments in selenium-containing polymeric micelles in light of their architecture, multiple stimuli-responsive properties, emerging immunomodulatory activities, and future perspectives in the delivery and controlled release of anticancer agents.

Bioinspired Composite, pH-Responsive Sodium Deoxycholate Hydrogel and Generation 4.5 Poly(amidoamine) Dendrimer Improves Cancer Treatment Efficacy via Doxorubicin and Resveratrol Co-Delivery.

Maximizing the antitumor efficacy of doxorubicin (DOX) with a new drug delivery strategy is always desired in the field of biomedical science. Because the clinical applications of DOX in the treatment of cancer is limited by the side effects related to the dose. Herein, we report the co-loading of DOX and resveratrol (RESV) using an injectable in situ formed sodium deoxycholate hydrogel (Na-DOC-hyd) at the pH of the tumor extracellular microenvironment. The sequential, controlled, and sustained release of RESV and DOX for synergistic antitumor effects was confirmed by entrapping G4.5-DOX in the RESV-loaded Na-DOC hydrogel (Na-DOC-hyd-RESV). The synergistic antitumor activity of Na-DOC-hyd-RESV+G4.5-DOX was assessed on HeLa cell xenograft tumor in BALB/c nude mice. In the MTT biocompatibility assay, both the G4.5 PAMAM dendrimer and Na-DOC-hyd exhibited negligible cytotoxicity up to the highest dose of 2.0 mg mL-1 in HeLa, MDA-MB-231, and HaCaT cells. The release profiles of DOX and RESV from the Na-DOC-hyd-RESV+G4.5-DOX confirmed the relatively rapid release of RESV (70.43 ± 1.39%), followed by that of DOX (54.58 ± 0.62%) at pH 6.5 in the 7 days of drug release studies. A single intratumoral injection of Na-DOC-hyd-RESV+G4.5-DOX maximally suppressed tumor growth during the 28 days of the treatment period. Na-DOC-hyd-RESV+G4.5-DOX did not cause any histological damage in the major visceral organs. Therefore, this Na-DOC-hydrogel for dual drugs (DOX and RESV) delivery at the pH of the tumor extracellular microenvironment is a promising, safe, and effective combination for antitumor chemotherapy.

Ibuprofen-Loaded Heparin Modified Thermosensitive Hydrogel for Inhibiting Excessive Inflammation and Promoting Wound Healing.

Hydrogels have been investigated as ideal biomaterials for wound treatment owing to their ability to form a highly moist environment which accelerates cell migration and tissue regeneration for prompt wound healing. They can also be used as a drug carrier for local delivery, and are able to activate immune cells to enhance wound healing. Here, we developed heparin-conjugated poly(N-isopropylacrylamide), an injectable, in situ gel-forming polymer, and evaluated its use in wound healing. Ibuprofen was encapsulated into the hydrogel to help reduce pain and excessive inflammation during healing. In addition to in vitro studies, a BALB/c mice model was used to evaluate its effect on would healing and the secretion of inflammatory mediators. The in vitro assay confirmed that the ibuprofen released from the hydrogel dramatically reduced lipopolysaccharide-induced inflammation by suppressing the production of NO, PGE2 and TNF-α in RAW264.7 macrophages. Moreover, an in vivo wound healing assay was conducted by applying hydrogels to wounds on the backs of mice. The results showed that the ibuprofen-loaded hydrogel improved healing relative to the phosphate buffered saline group. This study indicates that ibuprofen loaded in an injectable hydrogel is a promising candidate for wound healing therapy.

Fabrication of Core Crosslinked Polymeric Micelles as Nanocarriers for Doxorubicin Delivery: Self-Assembly, In Situ Diselenide Metathesis and Redox-Responsive Drug Release.

Polymeric micelles (PMs) have been used to improve the poor aqueous solubility, slow absorption and non-selective biodistribution of chemotherapeutic agents (CAs), albeit, they suffer from disassembly and premature release of payloads in the bloodstream. To alleviate the thermodynamic instability of PMs, different core crosslinking approaches were employed. Herein, we synthesized the poly(ethylene oxide)-b-poly((2-aminoethyl)diselanyl)ethyl l-aspartamide)-b-polycaprolactone (mPEG-P(LA-DSeDEA)-PCL) copolymer which self-assembled into monodispersed nanoscale, 156.57 ± 4.42 nm, core crosslinked micelles (CCMs) through visible light-induced diselenide metathesis reaction between the pendant selenocystamine moieties. The CCMs demonstrated desirable doxorubicin (DOX)-loading content (7.31%) and encapsulation efficiency (42.73%). Both blank and DOX-loaded CCMs (DOX@CCMs) established appreciable colloidal stability in the presence of bovine serum albumin (BSA). The DOX@CCMs showed redox-responsive drug releasing behavior when treated with 5 and 10 mM reduced glutathione (GSH) and 0.1% H2O2. Unlike the DOX-loaded non-crosslinked micelles (DOX@NCMs) which exhibited initial burst release, DOX@CCMs demonstrated a sustained release profile in vitro where 71.7% of the encapsulated DOX was released within 72 h. In addition, the in vitro fluorescent microscope images and flow cytometry analysis confirmed the efficient cellular internalization of DOX@CCMs. The in vitro cytotoxicity test on HaCaT, MDCK, and HeLa cell lines reiterated the cytocompatibility (≥82% cell viability) of the mPEG-P(LA-DSeDEA)-PCL copolymer and DOX@CCMs selectively inhibit the viabilities of 48.85% of HeLa cells as compared to 15.75% of HaCaT and 7.85% of MDCK cells at a maximum dose of 10 µg/mL. Overall, all these appealing attributes make CCMs desirable as nanocarriers for the delivery and controlled release of DOX in tumor cells.

Biotin-Decorated PAMAM G4.5 Dendrimer Nanoparticles to Enhance the Delivery, Anti-Proliferative, and Apoptotic Effects of Chemotherapeutic Drug in Cancer Cells.

Biotin receptors are overexpressed by various types of solid cancer cells and play a significant role in tumor metabolism, growth, and metastasis. Thus, targeting the biotin receptors on tumor cells may enhance the efficiency and reduce the side-effects of chemotherapy. The aim of this study was to develop a biotin-coupled poly(amido)amine (PAMAM) (PG4.5) dendrimer nanoparticle to enhance the tumor-specific delivery and intracellular uptake of anticancer drugs via receptor-mediated endocytosis. We modified PG4.5 with diethylenetriamine (DETA) followed by biotin via an amide bond and characterized the resulting PG4.5-DETA-biotin nanoparticles by 1H NMR, FTIR, and Raman spectroscopy. Loading and releasing of gemcitabine (GEM) from PG4.5-DETA-biotin were evaluated by UV-Visible spectrophotometry. Cell viability and cellular uptake were examined by MTT assay and flow cytometry to assess the biocompatibility, cellular internalization efficiency and antiproliferative activity of PG4.5-DETA-biotin/GEM. Gemcitabine-loaded PG4.5-DETA-biotin nanoparticles were spherical with a particle size of 81.6 ± 6.08 nm and zeta potential of 0.47 ± 1.25 mV. Maximum drug-loading content and encapsulation efficiency were 10.84 ± 0.16% and 47.01 ± 0.71%, respectively. Nearly 60.54 ± 1.99% and 73.96 ± 1.14% of gemcitabine was released from PG4.5-DETA-biotin/GEM nanoparticles after 48 h at the acidic pH values of 6.5 and 5, respectively. Flow cytometry and fluorescence microscopy of cellular uptake results revealed PG4.5-DETA-biotin/GEM nanoparticles selectively targeted cancer cells in vitro. Cytotoxicity assays demonstrated gemcitabine-loaded PG4.5-DETA-biotin significantly reduced cell viability and induced apoptosis in HeLa cells. Thus, biotin-coupled PG4.5-DETA nanocarrier could provide an effective, targeted drug delivery system and selectively convey gemcitabine into tumor cells.

In vitro siRNA delivery via diethylenetriamine- and tetraethylenepentamine-modified carboxyl group-terminated Poly(amido)amine generation 4.5 dendrimers.

The recent discovery of small interfering RNAs (siRNAs) has opened new avenues for designing personalized treatment options for various diseases. However, the therapeutic application of siRNAs has been confronted with many challenges because of short half-life in circulation, poor membrane penetration, difficulty in escaping from endosomes, and insufficient release into the cytosol. To overcome these challenges, we designed a diethylenetriamine (DETA)- and tetraethylenepentamine (TEPA)-modified polyamidoamine dendrimer generation 4.5 (PDG4.5), and characterized it using 1H nuclear magnetic resonance (NMR), 13C NMR, correlation spectroscopy (COSY), heteronuclear single-quantum correlation spectroscopy (HSQC), and Fourier transform infrared (FTIR) spectroscopy followed by conjugation with siRNA. The PDG4.5-DETA and PDG4.5-TEPA polyplexes exhibited spherical nanosize, ideal zeta potential, and effective siRNA binding ability, protected the siRNA from nuclease attack, and revealed less cytotoxicity of PDG4.5-DETA and PDG4.5-TEPA in HeLa cells. More importantly, the polyplexes also revealed good cellular internalization and facilitated translocation of the siRNA into the cytosol. Thus, PDG4.5-DETA and PDG4.5-TEPA can act as potential siRNA carriers in future medical and pharmaceutical applications.

Localized controlled release of bevacizumab and doxorubicin by thermo-sensitive hydrogel for normalization of tumor vasculature and to enhance the efficacy of chemotherapy.

In a malignant tumor, overexpression of pro-angiogenic factors like vascular endothelial growth factor (VEGF) provokes the production of pathologic vascular networks characterized by leaky, chaotically organized, immature, thin-walled, and ill-perfused. As a result, hostile tumor environment would be developed and profoundly hinders anti-cancer drug activities and fuels tumor progression. In this study, we develop a strategy of sequential sustain release of anti-angiogenic drug, Bevacizumab (BVZ), and anti-cancer drug, Doxorubicin (DOX), using poly (d, l-Lactide)- Poly (ethylene glycol) -Poly (d, l-Lactide) (PDLLA-PEG-PDLLA) hydrogel as a local delivery system. The release profiles of the drugs from the hydrogel were investigated in vitro which confirmed that relatively rapid release of BVZ (73.56 ±â€¯1.39%) followed by Dox (61.21 ±â€¯0.62%) at pH 6.5 for prolonged period. The in vitro cytotoxicity test revealed that the copolymer exhibited negligible cytotoxicity up to 2.5 mg ml-1 concentration on HaCaT and HeLa cells. Likeways, the in vitro degradation of the copolymer showed 41.63 ±â€¯2.62% and 73.25 ±â€¯4.36% weight loss within 6 weeks at pH 7.4 and 6.5, respectively. After a single intratumoral injection of the drug-encapsulated hydrogel on Hela xenograft nude, hydrogel co-loaded with BVZ and Dox displayed the highest tumor suppression efficacy for up to 36 days with no noticeable damage on vital organs. Therefore, localized co-delivery of anti-angiogenic drug and anti-cancer drug by hydrogel system may be a promising approach for enhanced chemotherapeutic efficacy in cancer treatment.

Encapsulation of gadolinium ferrite nanoparticle in generation 4.5 poly(amidoamine) dendrimer for cancer theranostics applications using low frequency alternating magnetic field.

Iron oxide-based magnetic resonance imaging (MRI) contrast agents have negative contrast limitations in cancer diagnosis. Gadolinium (Gd)-based contrast agents show toxicity. To overcome these limitations, Gd-doped ferrite (Gd:Fe3O4 (GdIO) nanoparticles (NPs) were synthesized as T1-T2 dual-modal contrast agents for MRI-traced drug delivery. A theranostics GdIO encapsulated in a Generation 4.5 PAMAM dendrimer (G4.5-GdIO) was developed by alkaline coprecipitation. The drug-loading efficiency of the NPs was ∼24%. In the presence of a low-frequency alternating magnetic field (LFAMF), a maximum cumulative doxorubicin (DOX) release of ∼77.47% was achieved in a mildly acidic (pH = 5.0) simulated endosomal microenvironment. Relaxometric measurements indicated superior r1 (5.19 mM-1s-1) and r2 (26.13 mM-1s-1) for G4.5-GdIO relative to commercially available Gd-DTPA. Thus, G4.5-GdIO is promising as an alternative noninvasive MRI-traced cancer drug delivery system.

Fabrication of redox-responsive Bi(mPEG-PLGA)-Se2 micelles for doxorubicin delivery.

Stimuli-responsive polymeric nanostructures have emerged as potential drug carriers for cancer therapy. Herein, we synthesized redox-responsive diselenide bond containing amphiphilic polymer, Bi(mPEG-PLGA)-Se2 from mPEG-PLGA and 3,3'-diselanediyldipropanoic acid (DSeDPA) using DCC/DMAP as coupling agents. Due to its amphiphilic nature, Bi(mPEG-PLGA)-Se2 self-assembled in to stable micelles in aqueous solution with a hydrodynamic size of 123.9 ±â€¯0.85 nm. The Bi(mPEG-PLGA)-Se2 micelles exhibited DOX-loading content (DLC) of 6.61 wt% and encapsulation efficiency (EE) of 54.9%. The DOX-loaded Bi(mPEG-PLGA)-Se2 micelles released 73.94% and 69.54% of their cargo within 72 h upon treatment with 6 mM GSH and 0.1% H2O2, respectively, at pH 7.4 and 37 °C. The MTT assay results demonstrated that Bi(mPEG-PLGA)-Se2 was devoid of any inherent toxicity and the DOX-loaded micelles showed pronounced antitumor activities against HeLa cells, 44.46% of cells were viable at maximum dose of 7.5 µg/mL. The cellular uptake experiment further confirmed the internalization of DOX-loaded Bi(mPEG-PLGA)-Se2 micelles and endowed redox stimuli triggered drug release in cytosol and nuclei of cancer cells. Overall, the results suggested that the smart, biocompatible Bi(mPEG-PLGA)-Se2 copolymer could serve as potential drug delivery biomaterial for the controlled release of hydrophobic drugs in cancer cells.

Redox-Responsive Heparin-Chlorambucil Conjugate Polymeric Prodrug for Improved Anti-Tumor Activity.

Polymeric prodrug-based delivery systems have been extensively studied to find a better solution for the limitations of a single drug and to improve the therapeutic and pharmacodynamics properties of chemotherapeutic agents, which can lead to efficient therapy. In this study, redox-responsive disulfide bond-containing amphiphilic heparin-chlorambucil conjugated polymeric prodrugs were designed and synthesized to enhance anti-tumor activities of chlorambucil. The conjugated prodrug could be self-assembled to form spherical vesicles with 61.33% chlorambucil grafting efficiency. The cell viability test results showed that the prodrug was biocompatible with normal cells (HaCaT) and that it selectively killed tumor cells (HeLa cells). The uptake of prodrugs by HeLa cells increased with time. Therefore, the designed prodrugs can be a better alternative as delivery vehicles for the chlorambucil controlled release in cancer cells.

In vivo antimalarial evaluation of some 2,3-disubstituted-4(3H)-quinazolinone derivatives.

BACKGROUND: Malaria is a neglected tropical parasitic disease affecting billons of people around the globe. Though the number of cases and deaths associated with malaria are decreasing in recent years, it is the most deadly disease in the world. This study aimed at investigating the in vivo antimalarial activities of some 2,3-disubstituted-4(3H)-quinazolinone derivatives. RESULTS: The in vivo antimalarial activities of the test compounds (6-9 and 11-13) were investigated using the 4-day suppressive standard test in mice infected with chloroquine-sensitive Plasmodium berghei ANKA strain. The tested compounds showed significant antimalarial activities with mean percentage suppression of 43.71-72.86 % which is significantly higher than the negative control group (p < 0.05). Compounds 12 and 13 displayed better antimalarial activities from the group with mean percentage suppression of 67.60 and 72.86 % respectively. CONCLUSION: The tested compounds showed significant in vivo antimalarial activities in mice infected with P. berghi ANKA strain. Thus, 3-aryl-2-(substitutedstyryl)-4(3H)-quinazolinones represent a possible scaffold for the development of antimalarial agents.