3 research outputs found
Chemical Approach to Positional Isomers of Glucose–Platinum Conjugates Reveals Specific Cancer Targeting through Glucose-Transporter-Mediated Uptake <i>in Vitro</i> and <i>in Vivo</i>
Glycoconjugation
is a promising strategy for specific targeting of cancer. In this
study, we investigated the effect of d-glucose substitution
position on the biological activity of glucose–platinum conjugates
(Glc-Pts). We synthesized and characterized all possible positional
isomers (C1α, C1β, C2, C3, C4, and C6) of a Glc-Pt. The
synthetic routes presented here could, in principle, be extended to
prepare glucose conjugates with different active ingredients, other
than platinum. The biological activities of the compounds were evaluated
both <i>in vitro</i> and <i>in vivo</i>. We discovered
that varying the position of substitution of d-glucose alters
not only the cellular uptake and cytotoxicity profile but also the
GLUT1 specificity of resulting glycoconjugates, where GLUT1 is glucose
transporter 1. The C1α- and C2-substituted Glc-Pts (<b>1α</b> and <b>2</b>) accumulate in cancer cells most efficiently
compared to the others, whereas the C3-Glc-Pt (<b>3</b>) is
taken up least efficiently. Compounds <b>1α</b> and <b>2</b> are more potent compared to <b>3</b> in DU145 cells.
The α- and β-anomers of the C1-Glc-Pt also differ significantly
in their cellular uptake and activity profiles. No significant differences
in uptake of the Glc-Pts were observed in non-cancerous RWPE2 cells.
The GLUT1 specificity of the Glc-Pts was evaluated by determining
the cellular uptake in the absence and in the presence of the GLUT1
inhibitor cytochalasin B, and by comparing their anticancer activity
in DU145 cells and a GLUT1 knockdown cell line. The results reveal
that C2-substituted Glc-Pt <b>2</b> has the highest GLUT1-specific
internalization, which also reflects the best cancer-targeting ability.
In a syngeneic breast cancer mouse model overexpressing GLUT1, compound <b>2</b> showed antitumor efficacy and selective uptake in tumors
with no observable toxicity. This study thus reveals the synthesis
of all positional isomers of d-glucose substitution for platinum
warheads with detailed glycotargeting characterization in cancer
Thieno-Pyrrole-Fused 4,4-Difluoro-4-bora-3a,4a-diaza‑<i>s</i>‑indacene–Fullerene Dyads: Utilization of Near-Infrared Sensitizers for Ultrafast Charge Separation in Donor–Acceptor Systems
Donor–acceptor
dyads featuring near-IR sensitizers derived
from thieno-pyrrole-fused BODIPY (abbreviated as SBDPiR) and fullerene,
C<sub>60</sub> have been newly synthesized and characterized. Occurrence
of ultrafast photoinduced electron transfer (PET) leading to the formation
of charge-separated state in these dyads, capable of harvesting light
energy from the near-IR region, is established from femtosecond transient
absorption studies
Maximizing Synergistic Activity When Combining RNAi and Platinum-Based Anticancer Agents
RNAi approaches have
been widely combined with platinum-based anticancer
agents to elucidate cellular responses and to target gene products
that mediate acquired resistance. Recent work has demonstrated that
platination of siRNA prior to transfection may negatively influence
RNAi efficiency based on the position and sequence of its guanosine
nucleosides. Here, we used detailed spectroscopic characterization
to demonstrate rapid formation of Pt-guanosine adducts within 30 min
after coincubation of oxaliplatin [OxaPtÂ(II)] or cisplatin [CisPtÂ(II)]
with either guanosine monophosphate or B-cell lymphoma 2 (BCL-2) siRNA.
After 3 h of exposure to these platinumÂ(II) agents, >50% of BCL-2
siRNA transcripts were platinated and unable to effectively suppress
mRNA levels. PlatinumÂ(IV) analogues [OxaPtÂ(IV) or CisPtÂ(IV)] did not
form Pt-siRNA adducts but did display decreased in vitro uptake and
reduced potency. To overcome these challenges, we utilized biodegradable
methoxyl-polyÂ(ethylene glycol)-<i>block</i>-polyÂ(ε-caprolactone)-<i>block</i>-polyÂ(l-lysine) (mPEG-<i>b</i>-PCL-<i>b</i>-PLL) to generate self-assembled micelles that covalently
conjugated OxaPtÂ(IV) and/or electrostatically complexed siRNA. We
then compared multiple strategies by which to combine BCL-2 siRNA
with either OxaPtÂ(II) or OxaPtÂ(IV). Overall, we determined that the
concentrations of siRNA (nM) and platinumÂ(II)-based anticancer agents
(μM) that are typically used for in vitro experiments led to
rapid Pt-siRNA adduct formation and ineffective RNAi. Coincorporation
of BCL-2 siRNA and platinumÂ(IV) analogues in a single micelle enabled
maximal suppression of BCL-2 mRNA levels (to <10% of baseline),
augmented the intracellular levels of platinum (by ∼4×)
and the numbers of resultant Pt-DNA adducts (by >5×), increased
the cellular fractions that underwent apoptosis (by ∼4×),
and enhanced the in vitro antiproliferative activity of the corresponding
platinumÂ(II) agent (by 10–100×, depending on the cancer
cell line). When combining RNAi and platinum-based anticancer agents,
this generalizable strategy may be adopted to maximize synergy during
screening or for therapeutic delivery