Multimodal Fluorescence and Bioluminescence Imaging Reveals Transfection Potential of Intratracheally Administered Polyplexes for Breast Cancer Lung Metastases

Geyer, Antonia; Taschauer, Alexander; Alioglu, Fatih; Anton, Martina; Maier, Julia; Drothler, Elisabeth; Simlinger, Manuela; Yavuz, Sümeyye; Sami, Haider; Ogris, Manfred

doi:10.1089/hum.2017.137

Cited by 11 publications

(23 citation statements)

References 29 publications

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“…At 11 days post tumor cell implantation, tumor nodules appeared as hyperintense areas at various regions in the lung (Figure 6B). Lung histopathology confirmed the findings by Geyer et al 19 . revealing both peribronchiolar and parenchymal tumor tissue with invasive growth pattern and accessibility from the alveolar side (Figures 6C and 6D).…”

Section: Resultssupporting

confidence: 88%

“…The tumor model was established by intravenous injection of 4T1-iRFP720 cells as recently described, 19 and tumor growth was monitored by T2-weighted MRI (Figure 6; Videos S1 and S2). On all T2-weighted MRI images, tumor tissue could be visualized as a hyperintense structure.…”

Section: Resultsmentioning

confidence: 99%

“…Also, in murine tumors, CD49f-high cells show tumor-initiating properties 16 and formation of metastasis 17 . The murine triple-negative breast cancer cell line 4T1 is a highly metastatic and aggressive cancer growing syngeneic in BALB/c mice forming lung metastasis accessible from the alveolar side 18 , 19 . Stable knockdown of CD49f in 4T1 reduced proliferation and migration in vitro 17 .…”

Section: Introductionmentioning

confidence: 99%

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Peptide-Targeted Polyplexes for Aerosol-Mediated Gene Delivery to CD49f-Overexpressing Tumor Lesions in Lung

Taschauer

Polzer

Alioglu

et al. 2019

Molecular Therapy - Nucleic Acids

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Peptide ligands can enhance delivery of nucleic acid-loaded nanoparticles to tumors by promoting their cell binding and internalization. Lung tumor lesions accessible from the alveolar side can be transfected, in principle, using gene vectors delivered as an aerosol. The cell surface marker CD49f (Integrin α6) is frequently upregulated in metastasizing, highly aggressive tumors. In this study, we utilize a CD49f binding peptide coupled to linear polyethylenimine (LPEI) promoting gene delivery into CD49f-overexpressing tumor cells in vitro and into lung lesions in vivo. We have synthesized a molecular conjugate based on LPEI covalently attached to the CD49f binding peptide CYESIKVAVS via a polyethylene glycol (PEG) spacer. Particles formed with plasmid DNA were small (<200 nm) and could be aerosolized without causing major aggregation or particle loss. In vitro, CD49f targeting significantly improved plasmid uptake and reporter gene expression on both human and murine tumor cell lines. For evaluation in vivo, localization and morphology of 4T1 murine triple-negative breast cancer tumor lesions in the lung of syngeneic BALB/c mice were identified by MRI. Polyplexes applied via intratracheal aerosolization were well tolerated and resulted in measurable transgene activity of the reporter gene firefly luciferase in tumor areas by bioluminescence imaging (BLI). Transfectability of tumors correlated with their accessibility for the aerosol. With CD49f-targeted polyplexes, luciferase activity was considerably increased and was restricted to the tumor area.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Peptide-Targeted Polyplexes for Aerosol-Mediated Gene Delivery to CD49f-Overexpressing Tumor Lesions in Lung

Taschauer

Polzer

Alioglu

et al. 2019

Molecular Therapy - Nucleic Acids

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“…To follow exact tumor growth, non-invasive DLIT combined with mCT 79 was performed using an IVIS Spectrum CT imaging system (IVIS Spectrum CT preclinical imaging system, Per-kinElmer Inc.) as previously described. 80 Briefly, mice were anaesthetized with 5 % of isoflurane (Isoflurane CP 1 ml/ml, CP-Pharma; #1214). Subsequently, D-luciferin bioluminescent substrate (D-Luciferin potassium salt, 120 mg/kg in PBS, Intrace Medical SA) was injected s.c.. DLIT was performed within 30 min post injection to guarantee a steady light emission.…”

Section: Dli/tmctmentioning

confidence: 99%

Bacterial ghosts as adjuvant to oxaliplatin chemotherapy in colorectal carcinomatosis

Groza

Gehrig

Kudela³

et al. 2018

OncoImmunology

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Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality worldwide. At late stage of the disease CRC often shows (multiple) metastatic lesions in the peritoneal cavity which cannot be efficiently targeted by systemic chemotherapy. This is one major factor contributing to poor prognosis. Oxaliplatin is one of the most commonly used systemic treatment options for advanced CRC. However, drug resistanceoften due to insufficient drug deliveryis still hampering successful treatment. The anticancer activity of oxaliplatin includes besides DNA damage also a strong immunogenic component. Consequently, the aim of this study was to investigate the effect of bacterial ghosts (BGs) as adjuvant immunostimulant on oxaliplatin efficacy. BGs are empty envelopes of gramnegative bacteria with a distinct immune-stimulatory potential. Indeed, we were able to show that the combination of BGs with oxaliplatin treatment had strong synergistic anticancer activity against the CT26 allograft, resulting in prolonged survival and even a complete remission in this murine model of CRC carcinomatosis. This synergistic effect was based on an enhanced induction of immunogenic cell death and activation of an efficient T-cell response leading to long-term anti-tumor memory effects. Taken together, co-application of BGs strengthens the immunogenic component of the oxaliplatin anticancer response and thus represents a promising natural immune-adjuvant to chemotherapy in advanced CRC.

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“…Delivery by microspray-based aerosolization via an intratracheal administration route is generally employed for proof-of-concept animal studies. 53 , 54 We have recently applied naked but chemically modified siRNA intratracheally demonstrating not only partial lung retention but also crossing of the air–blood barrier and renal excretion of intact siRNA. 24 Also, we could confirm that the AF750 dye remains attached to siRNA and the siRNA remains intact when analyzed in urine, making this a suitable method for tracking siRNA in vivo .…”

Section: Resultsmentioning

confidence: 99%

Combined Chemisorption and Complexation Generate siRNA Nanocarriers with Biophysics Optimized for Efficient Gene Knockdown and Air–Blood Barrier Crossing

Taschauer

Polzer

Pöschl

et al. 2020

ACS Appl. Mater. Interfaces

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Current nucleic acid (NA) nanotherapeutic approaches face challenges because of shortcomings such as limited control on loading efficiency, complex formulation procedure involving purification steps, low load of NA cargo per nanoparticle, endosomal trapping, and hampered release inside the cell. When combined, these factors significantly limit the amount of biologically active NA delivered per cell in vitro , delivered dosages in vivo for a prolonged biological effect, and the upscalability potential, thereby warranting early consideration in the design and developmental phase. Here, we report a versatile nanotherapeutic platform, termed auropolyplexes, for improved and efficient delivery of small interfering RNA (siRNA). Semitelechelic, thiolated linear polyethylenimine (PEI) was chemisorbed onto gold nanoparticles to endow them with positive charge. A simple two-step complexation method offers tunable loading of siRNA at concentrations relevant for in vivo studies and the flexibility for inclusion of multiple functionalities without any purification steps. SiRNA was electrostatically complexed with these cationic gold nanoparticles and further condensed with polycation or polyethyleneglycol–polycation conjugates. The resulting auropolyplexes ensured complete complexation of siRNA into nanoparticles with a high load of ∼15,500 siRNA molecules/nanoparticle. After efficient internalization into the tumor cell, an 80% knockdown of the luciferase reporter gene was achieved. Auropolyplexes were applied intratracheally in Balb/c mice for pulmonary delivery, and their biodistribution were studied spatio-temporally and quantitatively by optical tomography. Auropolyplexes were well tolerated with ∼25% of the siRNA dose remaining in the lungs after 24 h. Importantly, siRNA was released from auropolyplexes in vivo and a fraction also crossed the air–blood barrier, which was then excreted via kidneys, whereas >97% of gold nanoparticles were retained in the lung. Linear PEI-based auropolyplexes offer a combination of successful endosomal escape and better biocompatibility profile in vivo . Taken together, combined chemisorption and complexation endow auropolyplexes with crucial biophysical attributes, enabling a versatile and upscalable nanogold-based platform for siRNA delivery in vitro and in vivo .

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Multimodal Fluorescence and Bioluminescence Imaging Reveals Transfection Potential of Intratracheally Administered Polyplexes for Breast Cancer Lung Metastases

Cited by 11 publications

References 29 publications

Peptide-Targeted Polyplexes for Aerosol-Mediated Gene Delivery to CD49f-Overexpressing Tumor Lesions in Lung

Peptide-Targeted Polyplexes for Aerosol-Mediated Gene Delivery to CD49f-Overexpressing Tumor Lesions in Lung

Bacterial ghosts as adjuvant to oxaliplatin chemotherapy in colorectal carcinomatosis

Combined Chemisorption and Complexation Generate siRNA Nanocarriers with Biophysics Optimized for Efficient Gene Knockdown and Air–Blood Barrier Crossing

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