Chirality is ubiquitous in nature and hard-wired into every biological system. Despite the prevalence of chirality in biological systems, controlling biomaterial chirality to influence interactions with cells has only recently been explored. Here, we present chiral-engineered supraparticles (SPs) that interact differentially with cells and proteins depending on their handedness. SPs coordinated with Dchirality demonstrated greater than three-fold enhanced cell membrane penetration in breast, cervical, and multiple myeloma cancer cells. We carried out quartz crystal microbalance with dissipation and isothermal titration calorimetry measurements to understand the mechanism of these chiral-specific interactions. Thermodynamically, D-SPs showed more stable adhesion to lipid layers composed of phospholipids and cholesterol compared to L-SPs. In vivo, D-SPs exhibited superior stability and longer biological half-lives likely due to opposite chirality and thus protection from endogenous proteins including proteases. This work showed that incorporating D-chirality into nanosystems enhanced uptake by cancer cells and prolonged in vivo stability in circulation, providing support for the importance of chirality in biomaterials. Thus, chiral nanosystems may have the potential to provide a new level of control for drug delivery systems, tumor detection markers, biosensors, and other biomaterial based devices.
Mortalin/mthsp70 (HSPA9) is a stress chaperone enriched in many cancers that has been implicated in carcinogenesis by promoting cell proliferation and survival. In this study, we examined the clinical relevance of mortalin upregulation in carcinogenesis. Consistent with high mortalin expression in various human tumors and cell lines, we found that mortalin overexpression increased the migration and invasiveness of breast cancer cells. Expression analyses revealed that proteins involved in focal adhesion, PI3K-Akt, and JAK-STAT signaling, all known to play key roles in cell migration and epithelial-tomesenchymal transition (EMT), were upregulated in mortalinexpressing cancer cells. We further determined that expression levels of the mesenchymal markers vimentin (VIM), fibronectin (FN1), b-catenin (CTNNB1), CK14 (KRT14), and hnRNP-K were also increased upon mortalin overexpression, whereas the epithelial markers E-cadherin (CDH1), CK8 (KRT8), and CK18 (KRT18) were downregulated. Furthermore, shRNAmediated and pharmacologic inhibition of mortalin suppressed the migration and invasive capacity of cancer cells and was associated with a diminished EMT gene signature. Taken together, these findings support a role for mortalin in the induction of EMT, prompting further investigation of its therapeutic value in metastatic disease models. Cancer Res; 76(9);
Background: Mortalin/mtHsp70 is an essential stress chaperone frequently enriched in cancers. Results: Mortalin is present in the nucleus of cancer cells where it causes strong inactivation of tumor suppressor protein p53 and activation of telomerase and heterogeneous ribonucleoprotein K (hnRNP-K) proteins. Conclusion: Nuclear mortalin promotes carcinogenesis. Significance: This study is important for the development of mortalin-based anticancer treatments.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.