2 research outputs found
Redox-triggered mitoxantrone prodrug micelles for overcoming multidrug-resistant breast cancer
<p>Multidrug resistance (MDR) severely hinders the efficient chemotherapeutic treatments of cancer. d-α-Tocopherol polyethylene 1000 succinate (TPGS) based drug delivery system holds the potential of re-sensitizing resistant cancer cells. In this study, a TPGS prodrug containing both TPGS and mitoxantrone (MTO) via a disulphide bond was synthesised and assembled into micelle (TSMm) with a monodispersed diameter of 46.50 ± 1.12 nm. The disulphide bonds within the micelles could be cleaved in response to a high concentration of intracellular glutathione (GSH) after entering the tumour cells, leading a rapid release of MTO. <i>In vitro</i> cytotoxicity study showed TSMm significantly inhibited the growth of resistant breast tumour cells MDA-MB-231/MDR comparing to either free MTO or disulphide-free prodrug micelle (TCMm). In addition, TSMm could sustain favourable intracellular retention and cause the depletion of ATP activity, leading to the preferential transportation of MTO into the nucleus and the reversal of MDR. <i>In vivo</i> imaging also verified that TSMm was specifically targeted to the tumour regions at 24 h post injection. Finally, TSMm has significantly stronger antitumor activity in xenograft nude mice with negligible side effects. Hence, TSMm can serve as promising prodrug candidates to strengthen the reversal of MDR in tumours with less side effects.</p
Nanostructured Peptidotoxins as Natural Pro-Oxidants Induced Cancer Cell Death via Amplification of Oxidative Stress
Melittin
(Mel), one of the host defense peptides derived from the venom of
honeybees, demonstrates substantial anticancer properties, which is
attributed to augmenting reactive oxygen species (ROS) generation.
However, little has been reported on its pro-oxidation capacity in
cancer oxidation therapy. In this study, an ROS amplifying nanodevice
was fabricated through direct complexation of two natural pro-oxidants,
Mel and condensed epigallocatechin gallate (pEGCG). The obtained nanocomplex
(NC) was further covered with phenylboronic acid derivatized hyaluronic
acid (pHA) through the ROS-responsive boronate ester coordination
bond to produce pHA-NC. Upon undergoing receptor-mediated endocytosis
into cancer cells, the inner cores of pHA-NC will be partially uncovered
once pHA corona is degraded by hyaluronidase and will then escape
from the lysosome by virtue of cytolytic Mel. The elevated ROS level
in the tumor cytoplasm can disrupt the boronate ester bond to facilitate
drug release. Both Mel and pEGCG could synergistically amplify oxidative
stress and prolong ROS retention in cancer cells, leading to enhanced
anticancer efficacy. This ROS cascade amplifier based on selective
coordination bond and inherent pro-oxidation properties of natural
ingredients could detect and elevate intracellular ROS signals, potentiating
to move the tumor away from its homeostasis and make the tumor vulnerable.
Compared to previously reported chemosynthetic pro-oxidants, the ROS
self-sufficient system, fully composed of natural medicine, from this
study provides a new insight in developing cancer oxidation therapy