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J Control Release ; 318: 145-157, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31830540


Quantum dots offer superior optical features and hold a great potential as an imaging tool in comparison to 'conventional' fluorescent dyes. However, in vivo application in inflammatory-associated disorders is limited due to potential toxicity following systemic administration. Vascular inflammation contributes to cardiovascular diseases such as restenosis (re-narrowing of the artery following angioplasty), and poor prognosis is associated with the increased number of monocytes-derived macrophages (MDMs) in the arterial wall. Local administration of a suitable delivery system targeting MDMs could provide effective fluorescent imaging while minimizing systemic exposure and toxicity. We report here on the physicochemical characteristics and the structural stability of MDMs-targeted liposomal QDs (LipQDs), cellular uptake and cytotoxicity, the systemic biodistribution of LipQDs following local intra-luminal administration of LipQDs in carotid-injured rats vs. systemic administration, and imaging of QDs in the arterial tissue. The local treatment with LipQDs was found to be a suitable approach for targeting QDs to MDMs in the injured artery. In contrast to free QDs, the LipQDs formulation exhibited unique properties including structural and fluorescent stability, increased accumulation and retention for up to 24 h, and targeting properties enabling imaging of MDMs. MDMs imaging by targeted nanoparticles (NPs) could potentially serve for the detection of MDMs density in the injured artery for diagnostic purposes.

Nano Lett ; 19(9): 5844-5852, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31424944


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.

Lipossomos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Sistema Fagocitário Mononuclear/química , Pontos Quânticos/química , Animais , Vasos Sanguíneos/efeitos dos fármacos , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Lipídeos/química , Lipídeos/farmacologia , Lipossomos/química , Neoplasias Mamárias Animais/patologia , Camundongos , Nanomedicina , Células Neoplásicas Circulantes , Permeabilidade/efeitos dos fármacos
ACS Nano ; 11(3): 3038-3051, 2017 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-28196324


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.

Sistemas de Liberação de Medicamentos , Inflamação/diagnóstico por imagem , Monócitos/química , Monócitos/metabolismo , Imagem Óptica , Pontos Quânticos/química , Animais , Compostos de Cádmio/química , Células Cultivadas , Lipossomos/química , Lipossomos/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Ratos , Ratos Endogâmicos , Compostos de Selênio/química , Sulfetos/química , Distribuição Tecidual , Compostos de Zinco/química