In this study, doxorubicin (DOX) was conjugated to a lipophilic triphenylphosphonium (TPP) that is selectively taken up by the mitochondrial membrane of cells. This new derivative of DOX, i.e., TPP-DOX, was characterized by infrared spectroscopy (IR), nuclear magnetic resonance ((1)H NMR, (13)C NMR), and mass spectrometry. The effect of TPP modification on DOX cell uptake, intracellular trafficking, eventual DOX induced cytotoxicity, and the level of cleaved caspase 3 and PARP in wild type MDA-MB-435/WT and DOX resistant MDA-MB-435/DOX cells was then evaluated and compared to that for free DOX. In general, free DOX cellular uptake appeared to be significantly higher in MDA-MB-435/WT than MDA-MB-435/DOX cells. Moreover, free DOX was able to enter the nucleus of MDA-MB-435/WT cells, but in MDA-MB-435/DOX cells, it was confined within the cytoplasm. The TPP-DOX, on the other hand, was localized in the cytoplasm of both cell phenotypes and showed preferential distribution to the mitochondria. Correspondingly, in MDA-MB-435/DOX cells, an enhanced cytotoxicity was observed for TPP-DOX (IC50 of 33.6 and 21.0 μM at 48 and 72 h incubation, respectively) in comparison to free DOX (IC50 of 126.7 and 77.96 μM at 48 and 72 h incubation, respectively). This observation was accompanied by the increased level of cleaved caspase 3 and PARP indicating enhanced apoptosis in both cell lines, particularly that of MDA-MB-435/DOX, for TPP-DOX compared to free DOX following 24 h treatment. The present study highlights promising application of TPP-DOX in reversing drug resistance in tumor cells.

No abstract

Hypoxia-induced chemoresistance (HICR) is a well-recognized phenomenon, and in many experimental models, hypoxia inducible factor-1α (HIF-1α) is believed to be a key player. We aimed to better understand the mechanism underlying HICR in a triple negative breast cancer cell line, MDA-MB-231, with a focus on the role of HIF-1α. In this context, the effect of hypoxia on the sensitivity of MDA-MB-231 cells to cisplatin and their stem-like features was evaluated and the role of HIF-1α in both phenomena was assessed. Our results showed that hypoxia significantly increased MDA-MB-231 resistance to cisplatin. Correlating with this, intracellular uptake of cisplatin was significantly reduced under hypoxia. Furthermore, the stem-like features of MDA-MB-231 cells increased as evidenced by the significant increases in the expression of ATP-binding cassette (ABC) drug transporters, the proportion of CD44+/CD24− cells, clonogenic survival and cisplatin chemoresistance. Under hypoxia, both the protein level and DNA binding of HIF-1α was dramatically increased. Surprisingly, siRNA knockdown of HIF-1α did not result in an appreciable change to HICR. Instead, signal transducer and activator of transcription 3 (STAT3) activation was found to be important. STAT3 activation may confer HICR by upregulating ABC transporters, particularly ABCC2 and ABCC6. This study has demonstrated that, in MDA-MB-231 cells, STAT3 rather than HIF-1α is important in mediating HICR to cisplatin.

Viruses have recently emerged as promising nanomaterials for biotechnological applications. One of the most important applications of viruses is phage display, which has already been employed to identify a broad range of potential therapeutic peptides and antibodies, as well as other biotechnologically relevant polypeptides (including protease inhibitors, minimizing proteins, and cell/organ targeting peptides). Additionally, their high stability, easily modifiable surface, and enormous diversity in shape and size, distinguish viruses from synthetic nanocarriers used for drug delivery. Indeed, several plant and bacterial viruses (e.g., phages) have been investigated and applied as drug carriers. The ability to remove the genetic material within the capsids of some plant viruses and phages produces empty viral-like particles that are replication-deficient and can be loaded with therapeutic agents. This review summarizes the current applications of plant viruses and phages in drug discovery and as drug delivery systems and includes a discussion of the present status of virus-based materials in clinical research, alongside the observed challenges and opportunities.

No abstract

Our results imply a great potential for PolyGel TM formulations of silibinin for local treatment of malignant melanoma. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's content page.

The finding that hypoxia can induce cancer stemness in various experimental models is in agreement with the conceptual basis of cancer cell plasticity. Here, we aimed to gain insights into the molecular basis of hypoxia-induced cancer cell plasticity in triple negative breast cancer (TNBC). To achieve this goal, we employed our previously published in-vitro model of TNBC, in which a small subset of stem-like cells can be distinguished from the bulk cell population based on their responsiveness to a Sox2 reporter. In MDA-MB-231, a TNBC cell line, we observed that hypoxia significantly increased the expression of luciferase and green fluorescence protein (GFP), the readouts of the Sox2 reporter. Upon hypoxic challenge, the bulk, reporter unresponsive (RU) cells acquired stem-like features, as evidenced by the significant increases in the proportion of CD44 high /CD24 low cells, colony formation and resistance to cisplatin. Correlating with these phenotypic changes, RU cells exposed to hypoxia exhibited a substantial upregulation of the active/phosphorylated form of STAT3 (pSTAT3). This hypoxia-induced activation of STAT3 correlated with increased STAT3 transcriptional activity, as evidenced by increased STAT3-DNA binding and an altered gene expression profile. This hypoxia-induced STAT3 activation is biologically significant, since siRNA knockdown of STAT3 in RU cells significantly attenuated the hypoxia-induced acquisition of Sox2 activity and stem-like phenotypic features. In conclusion, our data have provided the proof-of-concept that STAT3 is a critical mediator in promoting the hypoxia-induced acquisition of cancer stemness in TNBC. Targeting STAT3 in TNBC may be useful in overcoming chemoresistance and decreasing the risk of disease relapse.

Stereoregularity of polymers is known to influence their physicochemical and functional properties in the bulk form. Recent studies have also provided evidence for the effect of polymer stereoregularity on the physicochemical and functional properties of their self-assembled nanostructures. Research in this area has witnessed a relatively rapid pace in the past few years; however, to the best of our knowledge, a proper review of the literature has not been made to date. The goal of this review article was to fill this gap and provide a detailed overview on the current knowledge and understanding on the effect of block copolymer stereoregularity on the properties of their self-assembled nanocarriers such as size, morphology, thermodynamic and kinetic stability, and drug loading and release. Emphasis is placed on poly(ester) containing block copolymers because of their safe history of human use and extensive application in drug delivery research.