Folate-targeted nanoparticles for rheumatoid arthritis therapy

Nogueira, E.; Gomes, Andreia C.; Preto, Ana; Cavaco-Paulo, Artur

doi:10.1016/j.nano.2015.12.365

Cited by 125 publications

(65 citation statements)

References 102 publications

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“…The strategy of incorporating a folic acid moiety into the P-Alexa647 copolymer was based on published observations that activation of macrophages, including TAMs, is associated with upregulation of folate receptor beta (FRb) on the cell surface (30). We speculated that inclusion of folic acid would favor driving the HPMA copolymer to TAMs in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…The strategy of incorporating folic acid into the P-Alexa647 construct is based upon the prior studies that activated macrophages in general, including TAMs, are associated with upregulation of folate receptor beta (FRb) on the cell surface (30). We sought to demonstrate, in vitro and in vivo , the preferential uptake of HPMA copolymers by TAMs utilizing in vivo infrared imaging, flow cytometry, qPCR, confocal fluorescent microscopy, and immunofluorescence modalities.…”

Section: Introductionmentioning

confidence: 99%

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HPMA–Copolymer Nanocarrier Targets Tumor-Associated Macrophages in Primary and Metastatic Breast Cancer

Zimel

Horowitz

Rajasekhar

et al. 2017

Molecular Cancer Therapeutics

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Polymeric nanocarriers such as N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers deliver drugs to solid tumors and avoid the systemic toxicity of conventional chemotherapy. Because HPMA copolymers can target sites of inflammation and accumulate within innate immune cells, we hypothesized that HPMA copolymers could target tumor-associated macrophages (TAMs) in both primary and metastatic tumor microenvironments. We verified this hypothesis, first in preliminary experiments with isolated bone marrow macrophage cultures in vitro, and subsequently in a spontaneously metastatic murine breast cancer model generated from a well-established, cytogenetically characterized 4T1 breast cancer cell line. Using our standardized experimental conditions, we detected primary orthotopic tumor growth at 7 days and metastatic tumors at 28 days after orthotopic transplantation of 4T1 cells into the mammary fat pad. We investigated the uptake of HPMA copolymer conjugated with Alexa Fluor 647 and folic acid (P-Alexa647-FA) and HPMA copolymer conjugated with IRDye 800CW (P-IRDye), following their retroorbital injection into the primary and metastatic tumor-bearing mice. A significant uptake of P-IRDye was observed at all primary and metastatic tumor sites in these mice, and the P-Alexa647-FA signal was found specifically within CD11b+TAMs co-stained with pan macrophage marker CD68. These findings demonstrate, for the first time, a novel capacity of a P-Alexa647-FA conjugate to colocalize to CD11b+CD68+ TAMs in both primary and metastatic breast tumors. This underscores the potential of this HPMA nanocarrier to deliver functional therapeutics that specifically target tumor-promoting macrophage activation and/or polarization during tumor development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HPMA–Copolymer Nanocarrier Targets Tumor-Associated Macrophages in Primary and Metastatic Breast Cancer

Zimel

Horowitz

Rajasekhar

et al. 2017

Molecular Cancer Therapeutics

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“…Only activated macrophages express folate receptor β (FR β), therefore, only macrophages actively involved in the inflammatory process are targeted. Administration of folic acid and MTX-conjugated poly(amidoamine) dendrimer (generation 5 [G5]) NP covalently conjugated to polyvalent folic acid (FA) (G5-FA-MTX) into CIA rats could selectively target and kill inflammatory macrophages with an important reduction of inflammation and arthritis clinical score (Nogueira, Gomes et al, 2016, Thomas, Goonewardena et al, 2011). MTX was also used in combination with human serum albumin NPs showing a significant delay in cartilage disruption in a humanized mouse model of RA (Fiehn, Neumann et al, 2004).…”

Section: The Use Of Nps For Anti-inflammatory Therapiesmentioning

confidence: 99%

Drug nanocarriers to treat autoimmunity and chronic inflammatory diseases

Prosperi

Colombo

Zanoni

et al. 2017

Seminars in Immunology

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Nanoparticles represent a new generation of drug delivery systems that can be engineered to harness optimal target selectivity for specific cells and tissues and high drug loading capacity, allowing for improved pharmacokinetics and enhanced bioavailability of therapeutics. The spontaneous propensity of both organic and colloidal nanoparticles to be captured by the cells of the reticuloendothelial system encouraged their utilization as passive targeting systems that can be preferentially directed to innate immune cells, such as macrophages, dendritic cells and neutrophils. The natural affinity for phagocytic cells suggests the possible implementation of nanoparticles as an immunotherapeutic platform for inflammatory diseases and autoimmune disorders. Here we discuss the recent advances in the application of nanotechnology to induce antigen-specific tolerance in autoimmunity and the use of nanoparticles for anti-inflammatory therapies, including treatment of inflammatory bowel diseases, psoriasis and rheumatoid arthritis.

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“…Several receptors such as CD44, CD64, folate receptor-beta (FR-β), vasoactive intestinal peptide (VIP) receptor, scavenger receptor class A, toll-like receptors, transforming growth factor-beta receptors, etc. were over-expressed on activated macrophages [1,[11][12][13][14][15][16].…”

Section: How To Design An Active Targeting Nanomedicine For Ra Treatmentmentioning

confidence: 99%

“…Rheumatoid arthritis (RA) is characterized by synovial inflammation and hyperplasia, autoantibody production, cartilage and bone destruction, and systemic features including cardiovascular, pulmonary, psychological, and skeletal disorders [1]. Currently, small-molecule disease-modifying anti-rheumatic drugs still serve as the first-line therapy.…”

Section: Introductionmentioning

confidence: 99%