Although liposomes are widely used as carriers of drugs and imaging agents, they suffer from a lack of stability and the slow release of the encapsulated contents at the targeted site. Polymersomes (vesicles of amphiphilic polymers) are considerably more stable compared to liposomes; however, they also demonstrate a slow release for the encapsulated contents, limiting their efficacy as a drug-delivery tool. As a solution, we prepared and characterized echogenic polymersomes which are programmed to release the encapsulated drugs rapidly when incubated with cytosolic concentrations of glutathione. These vesicles encapsulated air bubbles inside and efficiently reflected diagnostic frequency ultrasound. Folate-targeted polymersomes showed an enhanced uptake by breast and pancreatic-cancer cells in a monolayer as well as in three-dimensional spheroid cultures. Polymersomes encapsulated with the anticancer drugs gemcitabine and doxorubicin showed significant cytotoxicity to these cells. With further improvements, these vesicles hold the promise to serve as multifunctional nanocarriers, offering a triggered release as well as diagnostic ultrasound imaging.
The formation of melanoma metastases from primary tumor cells is a complex phenomenon that involves the regulation of multiple genes. We have previously shown that the receptor for advanced glycation end products (RAGE) was up-regulated in late metastatic stages of melanoma patient samples and we hypothesized that up-regulation of RAGE in cells forming a primary melanoma tumor could contribute to the metastatic switch of these cells. To test our hypothesis, we overexpressed RAGE in the WM115 human melanoma cell line that was established from a primary melanoma tumor of a patient. We show here that overexpression of RAGE in these cells is associated with mesenchymal-like morphologies of the cells. These cells demonstrate higher migration abilities and reduced proliferation properties, suggesting that the cells have switched to a metastatic phenotype. At the molecular level, we show that RAGE overexpression is associated with the up-regulation of the RAGE ligand S100B and the down-regulation of p53, ERK1/2, cyclin E and NF-kB. Our study supports a role of RAGE in the metastatic switch of melanoma cells.
Liposomes are representative lipid
nanoparticles widely used for
delivering anticancer drugs, DNA fragments, or siRNA to cancer cells.
Upon targeting, various internal and external triggers have been used
to increase the rate for contents release from the liposomes. Among
the internal triggers, decreased pH within the cellular lysosomes
has been successfully used to enhance the rate for releasing contents.
However, imparting pH sensitivity to liposomes requires the synthesis
of specialized lipids with structures that are substantially modified
at a reduced pH. Herein, we report an alternative strategy to render
liposomes pH sensitive by encapsulating a precursor which generates
gas bubbles in situ in response to acidic pH. The
disturbance created by the escaping gas bubbles leads to the rapid
release of the encapsulated contents from the liposomes. Atomic force
microscopic studies indicate that the liposomal structure is destroyed
at a reduced pH. The gas bubbles also render the liposomes echogenic,
allowing ultrasound imaging. To demonstrate the applicability of this
strategy, we have successfully targeted doxorubicin-encapsulated liposomes
to the pancreatic ductal carcinoma cells that overexpress the folate
receptor on the surface. In response to the decreased pH in the lysosomes,
the encapsulated anticancer drug is efficiently released. Contents
released from these liposomes are further enhanced by the application
of continuous wave ultrasound (1 MHz), resulting in substantially
reduced viability for the pancreatic cancer cells (14%).
Identification of pathogenic germline mutations by next generation sequencing is a widely accepted tool for predicting the risk of hereditary cancer development. Blood is the most common source of DNA for such tests. However, blood as a sample type has many drawbacks, including the invasive collection method, poor sample stability, and a relatively high cost of collection. Therefore, in the current study we have assessed the suitability of saliva as an alternative source of genomic DNA for the identification of germline mutations in the BRCA1/2 genes by next generation sequencing (NGS). Our results show that all of the samples yielded DNA concentrations sufficient for library preparation. The concentrations of the final libraries, which were generated by PCR using target specific primers, fall into the expected range with no notable difference between libraries generated from DNA derived from saliva or blood. Quality parameters indicate that sequencing performance is comparable across sample source. An average of (98 ± 0.02)% variant calling concordance was obtained between the two specimen sources. Our data recommends saliva as a potential alternative for detecting germline mutation by next generation sequencing.
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