Bioorthogonal Uncaging of the Active Metabolite of Irinotecan by Palladium‐Functionalized Microdevices

Abstract

SN‐38, the active metabolite of irinotecan, is released upon liver hydrolysis to mediate potent antitumor activity. Systemic exposure to SN‐38, however, also leads to serious side effects. To reduce systemic toxicity by controlling where and when SN‐38 is generated, a new prodrug was specifically designed to be metabolically stable and undergo rapid palladium‐mediated activation. Blocking the phenolic OH of SN‐38 with a 2,6‐bis(propargyloxy)benzyl group led to significant reduction of cytotoxic activity (up to 44‐fold). Anticancer properties were swiftly restored in the presence of heterogeneous palladium (Pd) catalysts to kill colorectal cancer and glioma cells, proving the efficacy of this novel masking strategy for aromatic hydroxyls. Combination with a Pd‐activated 5FU prodrug augmented the antiproliferative potency of the treatment, while displaying no activity in the absence of the Pd source, which illustrates the benefit of achieving controlled release of multiple approved therapeutics—sequentially or simultaneously—by the same bioorthogonal catalyst to increase anticancer activity.

Catalysis Concepts in Medicinal Inorganic Chemistry

“…Furthermore, ac ombination strategy where the irinotecan prodrug was administered with the propargyl-caged precursor of 5FU demonstrated to elicit a superior cytotoxic activity towardd ifferent cancerc ell lines in the presenceo fheterogenousPdc atalysts. [56] Besides Pd 0 catalysis, the group of Unciti-Broceta developed biocompatible Au resins for the catalytic deprotection of a range of propargyl-masked therapeuticsinv itro, including floxuridine, vorinostat, and doxorubicine. [57] Organopalladium catalysis was employed by Lv et al to activate an ewly designedp ropargyl-masked NO-releasing agent Figure 5).…”

“…The propargyl‐masked prodrug displayed reduced cytotoxic effects, yet its anticancer activity was restored in the presence of a Pd 0 catalyst. Furthermore, a combination strategy where the irinotecan prodrug was administered with the propargyl‐caged precursor of 5FU demonstrated to elicit a superior cytotoxic activity toward different cancer cell lines in the presence of heterogenous Pd catalysts …”

Cancer-derived exosomes loaded with ultrathin palladium nanosheets for targeted bioorthogonal catalysis

“…Pd, Ru, Au) have been shuttled into living cells, tissues and animals in pursuit of tools capable of catalysing first-in-life reactions. From organometallic complexes, [1][2][3][4][5][6][7][8][9][10][11][12][13] artificial metalloenzymes [14][15][16] and metal-loaded nanocarriers [17][18][19][20][21][22][23][24] to larger-than-cells implantable devices, [25][26][27][28][29][30][31] a selected number of agents have demonstrated catalytic activity and maintained their functional compatibility with the biological milieu. Although the development of effective intracellular catalysts based on abiotic metals remains challenging, various examples reported in the literature have tested the feasibility of this concept.…”

Bioorthogonal release of anticancer drugs via gold-triggered 2-alkynylbenzamide cyclization

“…In an emerging eld of study, researchers have extensively investigated metal-based uncaging of drugs/uorophores applicable in cell-or animal-based models. 3 Mainly employing metals like palladium and ruthenium, a number of examples have leaned heavily on some iteration of amine/alcohol release through masking groups that include azide, [4][5][6][7] allene, 8 allyl, 9,10 propargyl, [11][12][13][14][15][16][17][18][19][20][21][22] propargyloxycarbonyl (Proc), [19][20][21][22][23][24][25][26][27][28][29] and allyloxycarbonyl (Alloc). [10][11][12][28][29][30][31][32][33][34][35][36][37][38][39][40] Looking at current literature, a few areas of need can be clearly identied.…”