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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
Cancers (Basel) ; 11(4)2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934857


Non-viral, polymeric-based, siRNA nanoparticles (NPs) have been proposed as promising gene delivery systems. Encapsulating siRNA in targeted NPs could confer improved biological stability, extended half-life, enhanced permeability, effective tumor accumulation, and therapy. In this work, a peptide derived from apolipoprotein B100 (ApoB-P), the protein moiety of low-density lipoprotein, was used to target siRNA-loaded PEGylated NPs to the extracellular matrix/proteoglycans (ECM/PGs) of a mammary carcinoma tumor. siRNA against osteopontin (siOPN), a protein involved in breast cancer development and progression, was encapsulated into PEGylated poly(d,l-lactic-co-glycolic acid) (PLGA) NPs using the double emulsion solvent diffusion technique. The NPs obtained possessed desired physicochemical properties including ~200 nm size, a neutral surface charge, and high siOPN loading of ~5 µg/mg. ApoB-P-targeted NPs exhibited both enhanced binding to isolated ECM and internalization by MDA-MB-231 human mammary carcinoma cells, in comparison to non-targeted NPs. Increased accumulation of the targeted NPs was achieved in the primary mammary tumor of mice xenografted with MDA-MB-231 mammary carcinoma cells as well as in the lungs, one of the main sites affected by metastases. siOPN NPs treatment resulted in significant inhibition of tumor growth (similar bioactivity of both formulations), accompanied with significant reduction of OPN mRNA levels (~40% knockdown of mRNA levels). We demonstrated that targeted NPs possessed enhanced tumor accumulation with increased therapeutic potential in mice models of mammary carcinoma.

Drug Deliv Transl Res ; 8(4): 868-882, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29058205


Major advances have been achieved in understanding the mechanisms and risk factors leading to cardiovascular disorders and consequently developing new therapies. A strong inflammatory response occurs with a substantial recruitment of innate immunity cells in atherosclerosis, myocardial infarction, and restenosis. Monocytes and macrophages are key players in the healing process that ensues following injury. In the inflamed arterial wall, monocytes, and monocyte-derived macrophages have specific functions in the initiation and resolution of inflammation, principally through phagocytosis, and the release of inflammatory cytokines and reactive oxygen species. In this review, we will focus on delivery systems, mainly nanoparticles, for modulating circulating monocytes/monocyte-derived macrophages. We review the different strategies of depletion or modulation of circulating monocytes and monocyte subtypes, using polymeric nanoparticles and liposomes for the therapy of myocardial infarction and restenosis. We will further discuss the strategies of exploiting circulating monocytes for biological targeting of nanocarrier-based drug delivery systems for therapeutic and diagnostic applications.

Doenças Cardiovasculares/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Monócitos/imunologia , Animais , Doenças Cardiovasculares/imunologia , Humanos
Biomaterials ; 145: 154-167, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28863309


siRNA-loaded nanoparticles (NPs) administered systemically can overcome the poor stability and rapid elimination of free double-stranded RNA in circulation, resulting in increased tumor accumulation and efficacy. siRNA against osteopontin (siOPN), a protein involved in breast cancer development, was encapsulated in poly(D,L-lactic-co-glycolic acid) NPs by a double emulsion solvent diffusion (DESD) technique. We also compared the effect of polyethylenimine (PEI) molecular weight (800 Da and 25 kDa), used as the counter-ion for siRNA complexation, on the physicochemical properties of the NPs, cytotoxicity, and cellular uptake. NPs prepared by the DESD technique were obtained at the desired size (∼170 nm) using both types of PEIs, and were characterized with a neutral surface charge, high encapsulation yield (up to ∼60%), siOPN concentration of 5.6-8.4 µg/mg, stability in physiologic conditions in vitro and in vivo, and long-term shelf-life stability (> 3 years). The NPs prepared using both PEIs exhibited no cytotoxicity in primary smooth muscle culture, and no detrimental effect on mice liver enzymes following their IV administration. Following cellular uptake and biodistribution studies, the therapeutic potential of the NPs was demonstrated by a significant decrease of tumor progression and size in an ectopic xenograft model of mammary carcinoma in mice.

Emulsões/química , Ácido Láctico/química , Neoplasias Mamárias Experimentais/terapia , Nanopartículas/química , Ácido Poliglicólico/química , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/toxicidade , Solventes/química , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Difusão , Modelos Animais de Doenças , Endocitose/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Inativação Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Peso Molecular , Nanopartículas/ultraestrutura , Osteopontina/metabolismo , Tamanho da Partícula , Polietilenoimina/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Soro , Eletricidade Estática , Distribuição Tecidual/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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