16 research outputs found
6â˛â˛âThioether Tobramycin Analogues: Towards Selective Targeting of Bacterial Membranes
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91322/1/ange_201200761_sm_miscellaneous_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/91322/2/5750_ftp.pd
Image-guided surgery using near-infrared Turn-ON fluorescent nanoprobes for precise detection of tumor margins
Novel Pullulan Bioconjugate for Selective Breast Cancer Bone Metastases Treatment
A novel polysaccharide bioconjugate was designed to selectively target breast cancer bone metastases using a bisphosphonate moiety (alendronate, ALN). Paclitaxel (PTX) was first covalently conjugated to pullulan (Pull) through a Cathepsin K-sensitive tetrapeptide spacer followed by a self-immolative aminobenzyl alcohol spacer to obtain Pull-(GGPNle-phi-PTX). ALN was then conjugated to the polymeric backbone of Pull-(GGPNle-phi-PTX) via a PEG spacer. The final bioconjugate Pull-(GGPNle-phi-PTX)-(PEG-ALN) was found to assemble into colloidal spherical structures, which were physically and chemically stable under physiological conditions. In vitro studies showed that Pull-(GGPNle-phi-PTX)-(PEG-ALN) had strong affinity for hydroxyapatite, which simulates the bone tissue. Paclitaxel was rapidly released from the bioconjugate by Cathepsin K cleavage under pathological conditions. All studies performed using human MDA-MB-231-BM (bone metastases-originated clone), murine 4T1 breast cancer cells, murine K7M2, and human SAOS-2 osteosarcoma cells showed that the bioconjugate exerted an enhanced antiproliferative activity compared to the conjugate without the ALN. Furthermore, the nanoconjugate inhibited the migration of cancer cells and further displayed potent anti-angiogenic activity. In conclusion, the results showed that this conjugate has an excellent potential for selective treatment of bone neoplasms such as breast cancer bone metastases and osteosarcoma
Light emission enhancement by supramolecular complexation of chemiluminescence probes designed for bioimaging
The Role of PEDF in Reproductive Aging of the Ovary
Reproductive aging is characterized by a decline in ovarian function and in oocytesâ quantity and quality. Pigment epithelium-derived factor (PEDF), a pivotal player in ovarian angiogenic and oxidative balance, was evaluated for its involvement in reproductive aging. Our work examines the initial stage of reproductive aging in women and mice, and the involvement of PEDF in the process. Granulosa cells from reproductively-aged (RA) women and mice (36â44 years old and 9â10 months old, respectively) indicated an increase in the level of PEDF mRNA (qPCR), with yet unchanged levels of AMH and FSHR mRNAs. However, the PEDF protein level in individual women showed an intra-cellular decrease (ELISA), along with a decrease in the corresponding follicular fluid, which reflects the secreted fraction of the protein. The in vitro maturation (IVM) rate in the oocytes of RA mice was lower compared with the oocytes of young mice, demonstrated by a reduced polar body extrusion (PBE) rate. The supplementation of PEDF improved the hampered PBE rate, manifested by a higher number of energetically-competent oocytes (ATP concentration and mtDNA copy number of individual oocytes). Our findings propose PEDF as an early marker of reproductive aging, and a possible therapeutic in vitro agent that could enhance the number of good-quality oocytes in older IVF patients
Remarkable Enhancement of ChemiÂluminÂescent Signal by DioxetaneâFluorophore Conjugates: Turn-ON ChemiÂluminÂescence Probes with Color Modulation for Sensing and Imaging
ChemiÂluminÂescence
is among the most sensitive methods
for achieving a high signal-to-noise ratio in various chemical and
biological applications. We have developed a modular practical synthetic
route for preparation of turn-ON fluorophore-tethered dioxetane chemiÂluminÂescent
probes. The chemiÂluminÂescent emission of the probes was
significantly amplified through an energy-transfer mechanism under
physiological conditions. Two probes were composed with green and
near-infrared (NIR) fluorescent dyes tethered to Schaapâs dioxetane.
While both probes were able to provide chemiÂluminÂescence <i>in vivo</i> images following subÂcutaneous injection, only
the NIR probe could provide a chemiÂluminÂescence image
following intraÂperitoneal injection. These are the first <i>in vivo</i> images produced by Schaapâs dioxetane chemiÂluminÂescence
probes with no need of an enhancer. Previously, chemiÂluminÂescence
cell images could only be obtained with a luciferin-based probe. Our
NIR probe was able to image cells transfected with β-galactosidase
gene by chemiÂluminÂescence microscopy. We also report,
for the first time, the instability of dioxetaneâfluorophore
conjugates to ambient light. Our synthetic route effectively overcomes
this limitation through a late-stage functionalization of the dioxetane
intermediate. We anticipate that our practical synthetic methodology
will be useful for preparation of various chemiÂluminÂescent
probes for numerous applications
Poly(ethylene glycol)\u2013paclitaxel\u2013alendronate self-assembled micelles for the targeted treatment of breast cancer bone metastases
Paclitaxel (PTX) and alendronate (ALN) are effective drugs used for the treatment of breast cancer bone metastases. Growing evidence suggests that low-dose taxanes and bisphosphonates possess anti-angiogenic properties. However, PTX is water-insoluble and toxic, even if administered at anti-angiogenic dosing schedule. Polymer conjugation of PTX will increase water-solubility and improve its pharmacokinetic profile directing it to the tumor site. We further propose to combine it with ALN for active bone targeting. We conjugated ALN and PTX with poly(ethylene glycol) (PEG) forming self-assembled micelles where PTX molecules are located at the inner core and the water-soluble ALN molecules at the outer shell. PTX-PEG-ALN micelles exhibited similar in vitro cytotoxic and anti-angiogenic activity as the free drugs. Biodistribution analysis demonstrated preferential tumor accumulation of FITC-labeled PTX-PEG-ALN micelles. Pharmacokinetic studies revealed longer t1/2 of the conjugate than free PTX. PTX-PEG-ALN micelles achieved improved efficacy and safety profiles over free PTX in syngeneic and xenogeneic mouse models of mCherry-infected mammary adenocarcinoma in the tibia, as monitored intravitally non-invasively by a fluorescence imaging system. The described data warrants the potential use of PTX-PEG-ALN as bone-targeted anticancer and anti-angiogenic therapy for breast cancer bone metastases
Novel Pullulan Bioconjugate for Selective Breast Cancer Bone Metastases Treatment
A novel polysaccharide bioconjugate
was designed to selectively
target breast cancer bone metastases using a bisphosphonate moiety
(alendronate, ALN). Paclitaxel (PTX) was first covalently conjugated
to pullulan (Pull) through a Cathepsin K-sensitive tetrapeptide spacer
followed by a self-immolative aminobenzyl alcohol spacer to obtain
Pull-(GGPNle-Ď-PTX). ALN was then conjugated to the polymeric
backbone of Pull-(GGPNle-Ď-PTX) via a PEG spacer. The final
bioconjugate Pull-(GGPNle-Ď-PTX)-(PEG-ALN) was found to assemble
into colloidal spherical structures, which were physically and chemically
stable under physiological conditions. In vitro studies showed that
Pull-(GGPNle-Ď-PTX)-(PEG-ALN) had strong affinity for hydroxyapatite,
which simulates the bone tissue. Paclitaxel was rapidly released from
the bioconjugate by Cathepsin K cleavage under pathological conditions.
All studies performed using human MDA-MB-231-BM (bone metastases-originated
clone), murine 4T1 breast cancer cells, murine K7M2, and human SAOS-2
osteosarcoma cells showed that the bioconjugate exerted an enhanced
antiproliferative activity compared to the conjugate without the ALN.
Furthermore, the nanoconjugate inhibited the migration of cancer cells
and further displayed potent anti-angiogenic activity. In conclusion,
the results showed that this conjugate has an excellent potential
for selective treatment of bone neoplasms such as breast cancer bone
metastases and osteosarcoma
Inside Cover: 6â˛â˛âThioether Tobramycin Analogues: Towards Selective Targeting of Bacterial Membranes (Angew. Chem. Int. Ed. 23/2012)
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92017/1/5508_ftp.pd
Near-Infrared Dioxetane Luminophores with Direct Chemiluminescence Emission Mode
Chemiluminescent
luminophores are considered as one of the most
sensitive families of probes for detection and imaging applications.
Due to their high signal-to-noise ratios, luminophores with near-infrared
(NIR) emission are particularly important for <i>in vivo</i> use. In addition, light with such long wavelength has significantly
greater capability for penetration through organic tissue. So far,
only a few reports have described the use of chemiluminescence systems
for <i>in vivo</i> imaging. Such systems are always based
on an energy-transfer process from a chemiluminescent precursor to
a nearby emissive fluorescent dye. Here, we describe the development
of the first chemiluminescent luminophores with a direct mode of NIR
light emission that are suitable for use under physiological conditions.
Our strategy is based on incorporation of a substituent with an extended
Ď-electron system on the excited species obtained during the
chemiÂexcitation pathway of Schaapâs adamantÂylidene-dioxetane
probe. In this manner, we designed and synthesized two new luminophores
with direct light emission wavelength in the NIR region. Masking of
the luminophores with analyte-responsive groups has resulted in turn-ON
probes for detection and imaging of β-galactosidase and hydrogen
peroxide. The probesâ ability to image their corresponding
analyte/enzyme was effectively demonstrated <i>in vitro</i> for β-galactosidase activity and <i>in vivo</i> in
a mouse model of inflammation. We anticipate that our strategy for
obtaining NIR luminophores will open new doors for further exploration
of complex biomolecular systems using non-invasive intraÂvital
chemiluminescence imaging techniques