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, C₆₀ 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 [OxaPt­(II)] or cisplatin [CisPt­(II)] with either guanosine monophosphate or B-cell lymphoma 2 (BCL-2) siRNA. After 3 h of exposure to these platinum­(II) agents, >50% of BCL-2 siRNA transcripts were platinated and unable to effectively suppress mRNA levels. Platinum­(IV) analogues [OxaPt­(IV) or CisPt­(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-poly­(ethylene glycol)-<i>block</i>-poly­(ε-caprolactone)-<i>block</i>-poly­(l-lysine) (mPEG-<i>b</i>-PCL-<i>b</i>-PLL) to generate self-assembled micelles that covalently conjugated OxaPt­(IV) and/or electrostatically complexed siRNA. We then compared multiple strategies by which to combine BCL-2 siRNA with either OxaPt­(II) or OxaPt­(IV). Overall, we determined that the concentrations of siRNA (nM) and platinum­(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 platinum­(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 platinum­(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