12 research outputs found
SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion
Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era
Correction to “Intranuclear Drug Delivery and Effective in Vivo Cancer Therapy via Estradiol–PEG-Appended Multiwalled Carbon Nanotubes”
Surface Chemistry Dependent “Switch” Regulates the Trafficking and Therapeutic Performance of Drug-Loaded Carbon Nanotubes
The
present study explores the possibility of exploiting surface
functionality as one of the key regulators for modulating the intracellular
trafficking and therapeutic performance of drug loaded carbon nanotubes
(CNTs). In line with that approach, a series of biofunctionalized
multiwalled carbon nanotubes (f-CNTs <b>1</b>–<b>6</b>) decorated with various functional molecules including antifouling
polymer (PEG), tumor recognition modules (folic acid/hyaluronic acid/estradiol),
and fluorophores (rhodamine B isothiocyanate/Alexa Fluor) were synthesized.
By loading different anticancer agents (methotrexate (MTX), doxorubicin
(DOX), and paclitaxel (PTX)) onto each functionalized CNT preparation,
we tried to elucidate how the surface functional molecules associated
with each f-CNT influence their therapeutic potential. We observed
that antiproliferative or apoptotic activity of drug-loaded CNTs critically
depends on their mechanistic pathway of cellular internalization and
intracellular trafficking, which in turn had an intimate rapport with
their surface chemistry. To our knowledge, for the first time, we
have embarked on the possibility of using a surface chemistry dependent
“switch” to remote-control the second and third order
targeting of chemotherapeutic agents supramolecularly complexed/adsorbed
on CNTs, which in turn is expected to benefit the development of futuristic
nanobots for cancer theranostics
Hyaluronate Tethered, “Smart” Multiwalled Carbon Nanotubes for Tumor-Targeted Delivery of Doxorubicin
The present study reports the optimized synthesis, physicochemical
characterization, and biological evaluation of a novel, multiwalled
carbon nanotube-hyaluronic acid (MWCNT-HA) conjugate, complexed with
an anticancer agent, Doxorubicin (DOX) via π–π
stacking interaction. The therapeutic conjugate was concomitantly
labeled with a near-infrared fluorescent dye, Alexa-Flour-647 (AF-647),
and radiotracer Technetium-99m (<sup>99m</sup>Tc) to track its whereabouts
both in vitro and in vivo via optical and scintigraphic imaging techniques.
Covalent functionalization of MWCNTs with HA facilitated their internalization
into human lung adenocarcinoma, A549 cells via hyaluronan receptors
(HR) mediated endocytosis. Internalized nanotubes showed lysosomal
trafficking, followed by low pH-triggered DOX release under endolysosomal
conditions. Consequently, DOX-loaded HA-MWCNTs exhibited 3.2 times
higher cytotoxicity and increased apoptotic activity than free DOX
in equivalent concentrations. Organ distribution studies in Ehlrich
ascites tumor (EAT) bearing mice model indicated that tumor specific
localization of <sup>99m</sup>Tc-MWCNT-HA-DOX is significantly higher
than both free drug and nontargeted MWCNTs. Pharmacodynamic studies
in chemically breast-cancer-induced rats showed that the tumor-growth
inhibitory effect of HA-MWCNT-DOX was 5 times higher than free DOX
in equivalent concentration. DOX delivered through HA-MWCNTs was devoid
of any detectable cardiotoxity, hepatotoxicity, or nephrotoxicity.
All these promising attributes make HA-MWCNTs a “smart”
platform for tumor-targeted delivery of anticancer agents
Intranuclear Drug Delivery and Effective in Vivo Cancer Therapy via Estradiol–PEG-Appended Multiwalled Carbon Nanotubes
Cancer cell-selective, nuclear targeting is expected to enhance
the therapeutic efficacy of a myriad of antineoplastic drugs, particularly
those whose pharmacodynamic site of action is the nucleus. In this
study, a steroid-macromolecular bioconjugate based on PEG-linked 17β-Estradiol
(E<sub>2</sub>) was appended to intrinsically cell-penetrable multiwalled
carbon nanotubes (MWCNTs) for intranuclear drug delivery and effective
breast cancer treatment, both in vitro and in vivo. Taking Doxorubicin
(DOX) as a model anticancer agent, we tried to elucidate how E<sub>2</sub> appendage influences the cell internalization, intracellular
trafficking, and antitumor efficacy of the supramolecularly complexed
drug. We observed that the combination of DOX with E<sub>2</sub>-PEG-MWCNTs
not only facilitated nuclear targeting through an estrogen receptor
(ER)-mediated pathway but also deciphered to a synergistic anticancer
response in vivo. The antitumor efficacy of DOX@E<sub>2</sub>-PEG-MWCNTs
in chemically breast cancer-induced female rats was approximately
18, 17, 5, and 2 times higher compared to the groups exposed to saline,
drug-deprived E<sub>2</sub>-PEG-MWCNTs, free DOX, and DOX@m-PEG-MWCNTs,
respectively. While free DOX treatment induced severe cardiotoxicity
in animals, animals treated with DOX@m-PEG-MWCNTs and DOX@E<sub>2</sub>-PEG-MWCNTs were devoid of any perceivable cardiotoxicity, hepatotoxicity,
and nephrotoxicity. To the best of our knowledge, this is the first
instance in which cancer cell-selective, intranuclear drug delivery,
and, subsequently, effective in vivo breast cancer therapy has been
achieved using estrogen-appended MWCNTs as the molecular transporter
Augmented Anticancer Activity of a Targeted, Intracellularly Activatable, Theranostic Nanomedicine Based on Fluorescent and Radiolabeled, Methotrexate-Folic Acid-Multiwalled Carbon Nanotube Conjugate
The present study reports the design,
synthesis, and biological
evaluation of a novel, intravenously injectable, theranostic prodrug
based on multiwalled carbon nanotubes (MWCNTs) concomitantly decorated
with a fluorochrome (Alexa-fluor, AF488/647), radionucleide (Technitium-99m),
tumor-targeting module (folic acid, FA), and anticancer agent (methotrexate,
MTX). Specifically, MTX was conjugated to MWCNTs via a serum-stable
yet intracellularly hydrolyzable ester linkage to ensure minimum drug
loss in circulation. Cell uptake studies corroborated the selective
internalization of AF-FA-MTX-MWCNTs (<b>1</b>) by folate receptor
(FR) positive human lung (A549) and breast (MCF 7) cancer cells through
FR mediated endocytosis. Lysosomal trafficking of <b>1</b> enabled
the conjugate to exert higher anticancer activity as compared to its
nontargeted counterpart that was mainly restricted to cytoplasm. Tumor-specific
accumulation of <b>1</b> in Ehlrich Ascites Tumor (EAT) xenografted
mice was almost 19 and 8.6 times higher than free MTX and FA-deprived
MWCNTs. Subsequently, the conjugate <b>1</b> was shown to arrest
tumor growth more effectively in chemically breast tumor induced rats,
when compared to either free MTX or nontargeted controls. Interestingly,
the anticancer activities of the ester-linked CNT-MTX conjugates (including
the one deprived of FA) were significantly higher than their amide-linked
counterpart, suggesting that cleavability of linkers between drug
and multifunctional nanotubes critically influence their therapeutic
performance. The results were also supported by <i>in silico</i> docking and ligand similarity analysis. Toxicity studies in mice
confirmed that all CNT-MTX conjugates were devoid of any perceivable
hepatotoxicity, cardiotoxicity, and nephrotoxicity. Overall, the delivery
property of MWCNTs, high tumor binding avidity of FA, optical detectability
of AF fluorochromes, and radio-traceability of <sup>99m</sup>Tc could
be successfully integrated and partitioned on a single CNT-platform
to augment the therapeutic efficacy of MTX against FR overexpressing
cancer cells while allowing a real-time monitoring of treatment response
through multimodal imaging
Study of Different Crystal Habits of Aprepitant: Dissolution and Material Attributes
In the present study, aprepitant (APT) was selected to find its suitable crystal habit, which can improve its existing poor dissolution and manufacturing processability. Solvents were screened out for solubility analysis of APT and further crystal habit modification. Solid-state characterization studies like powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and Fourier infrared spectroscopy (FTIR) distinguished that tabular crystal habit was generated from acetone (APT-AC) and long tabular crystal habit was generated from ethyl acetate (APT-EA). Kawakita analysis and powder flow property studies showed that APT-EA is cohesive, has poor flow property and low bulk density compared to APT-AC (p < 0.05). Heckel plots reflected that APT-EA shows higher fragmentation and particle rearrangement during the initial stages as indicated by the higher intercept values. Higher slopes in APT-EA and APT-AC confirmed better plasticity but lower yield pressure in APT-AC proved good plastic deformation compared to APT-EA (p < 0.05). The dissolution profile of the APT-EA was found to be better than that of APT-AC. Overall, it can be concluded that APT-AC crystal habit has a better flow rate, tensile strength, and plasticity whereas APT-EA has better dissolution