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1.
J Control Release ; 318: 145-157, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31830540

RESUMO

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.

2.
Cancers (Basel) ; 11(4)2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934857

RESUMO

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.

3.
Drug Deliv Transl Res ; 8(4): 945-953, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28656488

RESUMO

The innate immunity system plays a critical role in vascular repair and restenosis development. Liposomes encapsulating bisphosphonates (LipBPs), but not free BPs, suppress neointima formation following vascular injury mediated in part by monocytes. The objective of this study was to elucidate the role of monocyte subpopulations on vascular healing following LipBP treatment. The potency- and dose-dependent treatment effect of clodronate (CLOD) and alendronate (ALN) liposomes on restenosis inhibition, total monocyte depletion, and monocytes subpopulation was studied. Rats subjected to carotid injury were treated by a single IV injection of LipBPs at the time of injury. Low- and high-dose LipALN treatment (3 and 10 mg/kg, respectively) resulted in a dose-dependent effect on restenosis development after 30 days. Both doses of LipALN resulted in a dose-dependent inhibition of restenosis, but only high dose of LipALN depleted monocytes (-60.1 ± 4.4%, 48 h post injury). Although LipCLOD treatment (at an equivalent potency to 3 mg/kg alendronate) significantly reduced monocyte levels (72.1 ± 6%), no restenosis inhibition was observed. The major finding of this study is the correlation found between monocyte subclasses and restenosis inhibition. Non-classical monocyte (NCM) levels were found higher in LipALN-treated rats, but lower in LipCLOD-treated rats, 24 h after injury and treatment. We suggest that the inhibition of circulating monocyte subpopulations is the predominant mechanism by which LipBPs prevent restenosis. The effect of LipBP treatment on the monocyte subpopulation correlates with the dose and potency of LipBPs.


Assuntos
Alendronato/administração & dosagem , Lesões das Artérias Carótidas/tratamento farmacológico , Ácido Clodrônico/administração & dosagem , Reestenose Coronária/prevenção & controle , Monócitos/imunologia , Lesões do Sistema Vascular/tratamento farmacológico , Animais , Lesões das Artérias Carótidas/imunologia , Lipossomos , Masculino , Ratos , Lesões do Sistema Vascular/imunologia
4.
Biomaterials ; 145: 154-167, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28863309

RESUMO

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.


Assuntos
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
5.
J Control Release ; 261: 138-146, 2017 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-28666727

RESUMO

Even though some progress in diagnosis and treatment has been made over the years, there is still no definitive treatment available for Glioblastoma multiforme (GBM). Convection-enhanced delivery (CED), a continuous infusion-mediated pressure gradient via intracranial catheters, studied in clinical trials, enables in situ drug concentrations several orders of magnitude greater than those achieved by systemic administration. We hypothesized that the currently limited efficacy of CED could be enhanced by a liposomal formulation, thus achieving enhanced drug localization to the tumor site with minimal toxicity. We hereby describe a novel approach for treating GBM by CED of liposomes containing the known chemotherapeutic agent, temozolomide (TMZ). A new technique for encapsulating TMZ in hydrophilic (PEGylated) liposomes, characterized by nano-size (121nm), low polydispersity index (<0.13) and with near-neutral charge (-ʒ,0.2mV), has been developed. Co-infusion of PEGylated Gd-DTPA liposomes and TMZ-liposomes by CED in GBM bearing rats, resulted in enhanced tumor detection with longer residence time than free Gd-DTPA. Treatment of GBM-bearing rats with either TMZ solution or TMZ-liposomes resulted in greater tumor inhibition and significantly higher survival. However, the longer survival and smaller tumor volumes exhibited by TMZ liposomal treatment in comparison to TMZ in solution were insignificant (p<0.053); and only significantly lower edema volumes were observed. Thus, there are no clear-cut advantages to use a liposomal delivery system of TMZ via CED over a drug solution.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Sistemas de Liberação de Medicamentos , Glioblastoma/tratamento farmacológico , Animais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Alquilantes/farmacologia , Convecção , Dacarbazina/administração & dosagem , Dacarbazina/farmacocinética , Dacarbazina/farmacologia , Gadolínio DTPA/administração & dosagem , Lipossomos , Masculino , Nanopartículas , Tamanho da Partícula , Polietilenoglicóis/química , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Taxa de Sobrevida , Temozolomida , Carga Tumoral
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