Quantum dots (QDs), semiconductor nanocrystals, are fluorescent nanoparticles of growing interest as an imaging tool of a diseased tissue. However, a major concern is their biocompatibility, cytotoxicity, and fluorescence instability in biological milieu, impeding their use in biomedical applications, in general, and for inflammation imaging, in particular. In addition, for an efficient fluorescent signal at the desired tissue, and avoiding systemic biodistribution and possible toxicity, targeting is desired. We hypothesized that phagocytic cells of the innate immunity system (mainly circulating monocytes) can be exploited as transporters of specially designed liposomes containing QDs to the inflamed tissue. We developed a liposomal delivery system of QDs (LipQDs) characterized with high encapsulation yield, enhanced optical properties including far-red emission wavelength and fluorescent stability, high quantum yield, and protracted fluorescent decay lifetime. Treatment with LipQDs, rather than free QDs, exhibited high accumulation and retention following intravenous administration in carotid-injured rats (an inflammatory model). QD-monocyte colocalization was detected in the inflamed arterial segment only following treatment with LipQDs. No cytotoxicity was observed following LipQD treatment in cell cultures, and changes in liver enzymes and gross histopathological changes were not detected in mice and rats, respectively. Our results suggest that the LipQD formulation could be a promising strategy for imaging inflammation.
The
majority of developed and approved anticancer nanomedicines
have been designed to exploit the dogma of the enhanced permeability
and retention (EPR) effect, which is based on the leakiness of the
tumor’s blood vessels accompanied by impeded lymphatic drainage.
However, the EPR effect has been under scrutiny recently because of
its variable manifestation across tumor types and animal species and
its poor translation to human cancer therapy. To facilitate the EPR
effect, systemically injected NPs should overcome the obstacle of
rapid recognition and elimination by the mononuclear phagocyte system
(MPS). We hypothesized that circulating monocytes, major cells of
the MPS that infiltrate the tumor, may serve as an alternative method
for achieving increased tumor accumulation of NPs, independent of
the EPR effect. We describe here the accumulation of liposomal quantum
dots (LipQDs) designed for active delivery via monocytes, in comparison
to LipQDs designed for passive delivery (via the EPR effect), following
IV administration in a mammary carcinoma model. Hydrophilic QDs were
synthesized and entrapped in functionalized liposomes, conferring
passive (“stealth” NPs; PEGylated, neutral charge) and
active (monocyte-mediated delivery; positively charged) properties
by differing in their lipid composition, membrane PEGylation, and
charge (positively, negatively, and neutrally charged). The various
physicochemical parameters affecting the entrapment yield and optical
stability were examined in vitro and in vivo. Biodistribution in the
blood, various organs, and in the tumor was determined by the fluorescence
intensity and Cd analyses. Following the treatment of animals (intact
and mammary-carcinoma-bearing mice) with disparate formulations of
LipQDs (differing by their lipid composition, neutrally and positively
charged surfaces, and hydrophilic membrane), we demonstrate comparable
tumor uptake of QDs delivered by the passive and the active routes
(mainly by Ly-6Chi monocytes). Our findings suggest that
entrapping QDs in nanosized liposomal formulations, prepared by a
new facile method, imparts superior structural and optical stability
and a suitable biodistribution profile leading to increased tumor
uptake of fluorescently stable QDs.
Hepatitis B virus has infected a third of the world’s population, and 296 million people are living with chronic infection. Chronic infection leads to progressive liver disease, including hepatocellular carcinoma and liver failure, and there remains no reliable curative therapy. These gaps in our understanding are due, in large part, to a paucity of animal models of HBV infection. Here, we show that rhesus macaques regularly clear acute HBV infection, similar to adult humans, but can develop long-term infection if immunosuppressed. Similar to patients, we longitudinally detected HBV DNA, HBV surface antigen, and HBV e antigen in the serum of experimentally infected animals. In addition, we discovered hallmarks of HBV infection in the liver, including RNA transcription, HBV core and HBV surface antigen translation, and covalently closed circular DNA biogenesis. This pre-clinical animal model will serve to accelerate emerging HBV curative therapies into the clinic.
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