Orally administered niclosamide-based organic/inorganic hybrid suppresses SARS-CoV-2 infection

The COVID-19 pandemic is a serious global health threat mainly due to the surging cases along with new variants of COVID-19. Though global vaccinations have indeed some effects on the virus spread, its longevity is still unknown. Therefore an orally administrable anti-viral agent against SARS-CoV-2 would be of substantial benefit in controlling the COVID-19 pandemic. Herein, we repurposed niclosamide (NIC), an FDA approved anthelmintic drug in to MgO, which was further coated with hydroxyl propyl methyl cellulose (HPMC) to get the de-sired product called NIC-MgO-HPMC, which has improved anti-SARS-CoV-2 replication in the Syrian hamster model. The inhibitory effect of NIC-MgO-HPMC on SARS-CoV-2 replication leads to the prevention of inflammation as well as lung injury. These data strongly support that repurposed NIC-MgO-HPMC could be highly beneficial for controlling the ongoing pandemic thereby achieving an endemic phase.

CD44 targeting biocompatible and biodegradable hyaluronic acid cross-linked zein nanogels for curcumin delivery to cancer cells: In vitro and in vivo evaluation.

In this study, we developed novel hyaluronic acid cross-linked zein nanogels (HA-Zein NGs) to deliver the potential anticancer agent curcumin (CRC), a naturally occurring phytochemical drug in cancer cells. In vitro studies showed that they are highly compatible with the tested cell lines. They showed CD44 specific uptake in CT26 cell line more than by the CD44 receptor pre-inhibited CT26 cells. The CRC encapsulated HA-Zein NGs (HA-Zein-CRC NGs) found to exert a specific toxicity against CT26 sparing healthy normal fibroblast cells in vitro. The apoptotic effects were further confirmed with flow cytometry showing that the HA-Zein-CRC NGs exhibited high anticancer activity against the CT26 cells. The in vivo bio-distribution with a CT26 tumor model showed their high tumor accumulation thereby improved antitumor efficacy with a low dosage of CRC, compared to the previous reports. Thus, the preclinical studies clearly showed that these novel HA-Zein NGs would be highly beneficial in encapsulating hydrophobic drugs with improved pharmacokinetics thereby enhancing the therapeutic outcomes.

Protease-activatable cell-penetrating peptide possessing ROS-triggered phase transition for enhanced cancer therapy.

Reactive oxygen species (ROS)- or protease-responsive materials have been utilized as carriers in cancer therapies because ROS and specific proteases are overproduced in cancer cells. Methionine-based polypeptides containing a thioether group are promising candidates due to their ROS-responsiveness which provides a phase transition. Herein, we developed protease-activatable cell-penetrating peptide containing a ROS-responsive methionine, a cell permeable lysine chain, and a matrix metalloproteinase (MMP)-cleavable linker. We designed a poly(l-methionine-block-l-lysine)-PLGLAG-PEG (MLMP) and doxorubicin (DOX) was loaded into the micelle core. The MLMP exhibited MMP-sensitive cleavage and ROS-induced DOX release. Moreover, we confirmed efficient DOX delivery into cancer cells and induction of the apoptotic capability in vitro. In a bio-distribution study, IR-780 dye encapsulated MLMP showed superior tumor targetability with long retention. Furthermore, MLMP (DOX) exhibited outstanding tumor inhibition capability with non-toxicity compared to free DOX, indicating that dual stimuli-MLMP has great potential as an anticancer drug delivery platform.

Anti-cancer, pharmacokinetics and tumor localization studies of pH-, RF- and thermo-responsive nanoparticles.

The curcumin-encapsulated chitosan-graft-poly(N-vinyl caprolactam) nanoparticles containing gold nanoparticles (Au-CRC-TRC-NPs) were developed by ionic cross-linking method. After "optimum RF exposure" at 40 W for 5 min, Au-CRC-TRC-NPs dissipated heat energy in the range of ∼42°C, the lower critical solution temperature (LCST) of chitosan-graft-poly(N-vinyl caprolactam), causing controlled curcumin release and apoptosis to cancer cells. Further, in vivo PK/PD studies on swiss albino mice revealed that Au-CRC-TRC-NPs could be sustained in circulation for a week with no harm to internal organs. The colon tumor localization studies revealed that Au-CRC-TRC-NPs were retained in tumor for a week. These results throw light on their feasibility as multi-responsive nanomedicine for RF-assisted cancer treatment modalities.

Synthesis, characterization and biological activities of curcumin nanospheres.

Curcumin is one of the most versatile compounds obtained from Curcuma longa. The major obstacle in the therapeutic use of curcumin is its aqueous solubility. To enhance its aqueous solubility and biological activities, we prepared curcumin nanospheres (CNSs) by wet milling-solvent evaporation technique without any surfactants. In this study, we have focused on the synthesis, characterization and biological effects of CNSs. DLS and SEM analyses showed 50-80 nm spherical shaped CNSs with a zeta potential of -31.65 mV. FTIR revealed that there were no structural changes to CNSs. Antibacterial and antifungal studies proved that CNSs were much more effective than curcumin against Escherichia coil, Staphylococcus aureus and Candida albicans. Antioxidant activity of CNSs showed promising result for therapeutic applications. The in vitro anti-inflammatory studies proved that CNSs possessed enhanced anti-inflammatory effect against protein denaturation. Cytotoxicity and uptake of CNSs showed more toxicity on cancer cells (T47D, MG63, A375) sparing normal HDF and IEC cell lines. Skin permeation studies showed CNSs retained at different layers of pig skin. These results give clear evidence for their use against microbial and fungal skin infections as well as cancer treatment.

Bio-responsive chitin-poly(L-lactic acid) composite nanogels for liver cancer.

Hepatic carcinoma (HCC) is one of the most common cancer and its treatment has been considered a therapeutic challenge. Doxorubicin (Dox) is one of the most important chemotherapeutic agents used in the treatment for liver cancer. However, the efficacy of Dox therapy is restricted by the dose-dependent toxic side effects. To overcome the cardiotoxicity of Dox as well as the current problems of conventional modality treatment of HCC, we developed a locally injectable, biodegradable, and pH sensitive composite nanogels for site specific delivery. Both control and Dox loaded composite nanogel systems were analyzed by DLS, SEM, FTIR and TG/DTA. The size ranges of the control composite nanogels and their drug loaded counterparts were found to be 90±20 and 270±20 nm, respectively. The control chitin-PLA CNGs and Dox-chitin-PLA CNGs showed higher swelling and degradation in acidic pH. Drug entrapment efficiency and in vitro drug release studies were carried out and showed a higher drug release at acidic pH compared to neutral pH. Cellular internalization of the nanogel systems was confirmed by fluorescent microscopy. The cytotoxicity of the composite nanogels was analyzed toward HepG2 (human liver cancer) cell lines. Furthermore, the results of in vitro hemolytic assay and coagulation assay substantiate the blood compatibility of the system. Overall Dox-chitin-PLA CNGs system could be a promising anticancer drug delivery system for liver cancer therapy.

Doxorubicin-chitin-poly(caprolactone) composite nanogel for drug delivery.

In this work, we developed a pH responsive chitin-poly(caprolactone) composite nanogels (chitin-PCL CNGs) system for non-small cell lung cancer (NSCLC). A hydrophilic drug, doxorubicin (Dox) was loaded in Chitin-PCL CNGs (Dox-chitin-PCL CNGs). Both control and drug loaded systems were analyzed by DLS, SEM, FTIR and TG/DTA. The size ranges of the control composite nanogels and their drug loaded counterparts were found to be 70 ± 20 and 240 ± 20 nm, respectively. The control chitin-PCL CNGs and Dox-chitin-PCL CNGs showed higher swelling and degradation in acidic pH. Drug entrapment efficiency and in-vitro drug release studies were carried out and showed a higher drug release at acidic pH compared to neutral pH. Cellular internalization of the nanogel systems was confirmed by fluorescent microscopy. Dox-Chitin-PCL CNGs showed dose dependent cytotoxicity toward A549 (adenocarcinomic human alveolar basal epithelial cells) cancer cells. Furthermore, the results of in-vitro hemolytic assay and coagulation assay substantiate the blood compatibility of the system. These results indicate that chitin-PCL CNGs is a novel carrier for delivery of anticancer drugs.

Cetuximab conjugated O-carboxymethyl chitosan nanoparticles for targeting EGFR overexpressing cancer cells.

Nanoparticle mediated delivery of antineoplastic agents, functionalized with monoclonal antibodies has achieved extraordinary potential in cancer therapy. The objective of this study was to develop a drug delivery system comprising O-carboxymethyl chitosan (O-CMC) nanoparticles, surface-conjugated with Cetuximab (Cet) for targeted delivery of paclitaxel (PTXL) to Epidermal Growth Factor Receptor (EGFR) over-expressing cancer cells. Nanoparticles around 180±35nm and negatively charged were prepared through simple ionic gelation technique. The alamar blue assay indicated that these targeted nanoparticles displayed a superior anticancer activity compared to non-targeted nanoparticles. The nanoformulation triggered enhanced cell death (confirmed by flow cytometry) due to its higher cellular uptake. The selective uptake of Cet-PTXL-O-CMC nanoparticles by EGFR +VE cancer cells (A549, A431 and SKBR3) compared to EGFR -VE MIAPaCa-2 cells confirms the active targeting and delivery of PTXL via the targeted nanomedicine. Cet-PTXL-O-CMC nanoparticles can be used a promising candidate for the targeted therapy of EGFR over expressing cancers.

Development and evaluation of 5-fluorouracil loaded chitin nanogels for treatment of skin cancer.

This study focuses on development and evaluation of 5-fluorouracil (5-FU) loaded chitin nanogels (FCNGs). It formed good, stable aqueous dispersion with spherical particles in 120-140 nm size range and showed pH responsive swelling and drug release. The FCNGs showed toxicity on melanoma (A375) in a concentration range of 0.4-2.0mg/mL, but less toxicity toward human dermal fibroblast (HDF) cells by MTT assay. Confocal analysis revealed uptake of FCNGs by both cells. From skin permeation experiments, FCNGs showed almost same steady state flux as that of control 5-FU but the retention in the deeper layers of skin was found to be 4-5 times more from FCNGs. Histopathological evaluation revealed loosening of the horny layer of epidermis by interaction of cationically charged chitin, with no observed signs of inflammation and so FCNGs can be a good option for treatment of skin cancers.