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Peptide mediated active targeting and intelligent particle size reduction-mediated enhanced penetrating of fabricated nanoparticles for triple-negative breast cancer treatment.

ABSTRACT: Triple-negative breast cancer (TNBC) is one of the most invasively malignant human cancers and its incidence increases year by year. Effective therapeutics against them needs to be developed urgently. In this study, a kind of angiopep-2 modified and intelligently particle size-reducible NPs, Angio-DOX-DGL-GNP, was designed for accomplishing both high accumulation and deep penetration within tumor tissues. On one hand, for improving the cancerous targeting efficiency of NPs, angiopep-2 was anchored on the surface of NPs to facilitate their accumulation via binding with low density lipoprotein-receptor related protein (LRP) overexpressed on TNBC. On the other hand, for achieving high tumor retention and increasing tumor penetration, an intelligently particle size-reducible NPs were constructed through fabricating gelatin NPs (GNP) with doxorubicin (DOX) loaded dendrigraft poly-lysine (DGL). In vitro cellular uptake and ex-vivo imaging proved the tumor targeting effect of Angio-DOX-DGL-GNP. Additionally, the degradation of large-sized Angio-DOX-DGL-GNP by matrix metalloproteinase-2 (MMP-2) led to the size reduction from 185.7 nm to 55.6 nm. More importantly, the penetration ability of Angio-DOX-DGL-GNP after incubation with MMP-2 was dominantly enhanced in tumor spheroids. Due to a combinational effect of active targeting and deep tumor penetration, the tumor growth inhibition rate of Angio-DOX-DGL-GNP was 74.1% in a 4T1 breast cancer bearing mouse model, which was significantly higher than other groups. Taken together, we successfully demonstrated a promising and effective nanoplatform for TNBC treatment.

SUBMITTER: Hu G

PROVIDER: S-EPMC4747404 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Peptide mediated active targeting and intelligent particle size reduction-mediated enhanced penetrating of fabricated nanoparticles for triple-negative breast cancer treatment.

Hu Guanlian G Chun Xingli X Wang Yang Y He Qin Q Gao Huile H

Oncotarget 20151201 38

Triple-negative breast cancer (TNBC) is one of the most invasively malignant human cancers and its incidence increases year by year. Effective therapeutics against them needs to be developed urgently. In this study, a kind of angiopep-2 modified and intelligently particle size-reducible NPs, Angio-DOX-DGL-GNP, was designed for accomplishing both high accumulation and deep penetration within tumor tissues. On one hand, for improving the cancerous targeting efficiency of NPs, angiopep-2 was anchor ...[more]

PMID: 26517810

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Project description:PurposeTo compare the amount of myopia induced by same-size donor-to-host penetrating keratoplasty with that of the amount of myopia induced by over-sized donor-to-host penetrating keratoplasty.SettingTertiary referral academic center.DesignRetrospective cohort study.MethodsCharts from patients who underwent penetrating keratoplasty by the same technique at Bascom Palmer Eye Institute between Nov 1, 2002, and January 1, 2006, were reviewed. The patients underwent optical penetrating keratoplasty using 12 interrupted 10-0 nylon sutures and a 12-bite continuous 10-0 nylon suture by a single surgeon (R.K.F.). The surgical technique used would be considered standard of care at most institutions. The Institutional Review Board, University of Miami Human Subjects Research Office, approved the study protocol. The donor graft was over-sized by 0.25mm in eyes when the intended final refractive target was greater than -1.00 diopters spherical equivalent (SE). The same-size donor graft was used when the intended final refractive target was less than -1.00 diopters SE. The selection of donor graft size was entirely based upon clinical parameters, meaning that the intended final refractive target was determined per each patient's fellow eye refraction, with the intention of reducing anisometropia. All patients received postoperative refraction and corneal topography. These measurements were performed at 6-8 weeks when the initial removal of sutures commenced, then at 6 months, then after completion of selective suture removal, then again at 12 months.ResultsAt 12 months, the over-sized group resulted in -1.35 diopters (SD = 2.25) SE of refraction, and the same-size group resulted in -0.14 diopters (SD = 2.42) SE. This approached statistical significance (p = 0.052) in comparison to -1.00 diopters spherical equivalent.ConclusionsUsing a donor graft that is over-sized by 0.25mm results in refraction of -1.00 diopters SE or more of myopia. Using a same-size donor-graft results in refraction of less than -1.00 diopters SE. Therefore, careful graft-size selection can result in a more favorable clinical outcome-namely, reduction in anisometropia-in patients undergoing penetrating keratoplasty.

Project description:Breast cancer remains a complex disease resulting in high mortality in women. A subset of cancer stem cell (CSC)-like cells expressing aldehyde dehydrogenase 1 (ALDH1) and SOX2/OCT4 are implicated in aggressive biology of specific subtypes of breast cancer. Targeting these populations in breast tumors remain challenging. We examined xenografts from three poorly studied triple negative (TN) breast cancer cells (MDA-MB-468, HCC70 and HCC1806) as well as HMLEHRASV12 for stem cell (SC)-specific proteins, proliferation pathways and dual-specific phosphatases (DUSPs) by quantitative real-time PCR (qRT-PCR), immunoblot analysis and immunohistochemistry. We found that pERK1/2 remained suppressed in TN xenografts examined at various stages of growth, while the levels of pp38 MAPK and pAKT was upregulated. We found that DUSP was involved in the suppression of pERK1/2, which was MEK1/2 independent. Our in vitro assays, using HMLEHRASV12 xenografts as a positive control, confirmed increased phosphatase activity that specifically influenced pERK1/2 but not pp38MAPK or pJNK levels. Family members of DUSPs examined, showed increase in DUSP9 expression in TN xenografts. Increased DUSP9 expression in xenografts was consistently associated with upregulation of SC-specific proteins, ALDH1 and SOX2/OCT4. HRAS driven HMLEHRASV12 xenografts as well as mammospheres from TN breast cancer cells showed inverse relationship between pERK1/2 and increased expression of DUSP9 and CSC traits. In addition, treatment in vitro, with MEK1/2 inhibitor, PD 98059, reduced pERK1/2 levels and increased DUSP9 and SC-specific proteins. Depletion of subsets of SOX2/OCT4 by fluorescence-activated cell sorting (FACS), as well as pharmacological and genetic reduction of DUSP9 levels influenced ALDH1 and SOX2/OCT4 expression and reduced mammosphere growth in vitro as well as tumor growth in vivo. Collectively our data support the possibility that DUSP9 contributed to stem cell-like cells that could influence TN breast tumor growth. Conclusion: Our study shows that subsets of TN breast cancers with MEK1/2 independent reduced pERK1/2 levels will respond less to MEK1/2 inhibitors, thereby questioning their therapeutic efficacy. Our study also demonstrates context-dependent DUSP9-mediated reduced pERK1/2 levels could influence stem cell-like traits in TN breast tumors. Therefore, targeting DUSP9 could be an attractive target for improved clinical outcome in a subset of basal-like breast cancers.

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Peptide mediated active targeting and intelligent particle size reduction-mediated enhanced penetrating of fabricated nanoparticles for triple-negative breast cancer treatment.

Publications

Peptide mediated active targeting and intelligent particle size reduction-mediated enhanced penetrating of fabricated nanoparticles for triple-negative breast cancer treatment.

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