Activated macrophages overexpress the folate receptor β (FR-β) that can be used for targeted delivery of drugs conjugated to folic acid. FR-expressing macrophages contribute to arthritis progression by secreting prostaglandin E₂ (PGE₂). Non-steroidal anti-inflammatory drugs (NSAIDs) block PGs and thromboxane by inhibiting the cyclooxygenase (COX) enzymes and are used for chronic pain and inflammation despite their well-known toxicity. New NSAIDs target an enzyme downstream of COXs, microsomal prostaglandin E synthase-1 (mPGES-1). Inhibition of mPGES-1 in inflammatory macrophages promises to retain NSAID efficacy while limiting toxicity. We conjugated a potent mPGES-1 inhibitor, MK-7285, to folate, but the construct released the drug inefficiently. Folate conjugation to the primary alcohol of MK-7285 improved the construct’s stability and the release of free drug. Surprisingly, the drug-folate conjugate potentiated PGE₂ in FR-positive KB cells, and reduced PGE₂ in macrophages independently of the FR. Folate conjugation of NSAIDs is not an optimal strategy for targeting of macrophages.

活化的巨噬细胞过表达叶酸受体 β (FR-β)，可用于靶向递送与叶酸结合的药物。表达 FR 的巨噬细胞通过分泌前列腺素 E ₂ (PGE ₂）。非甾体抗炎药 (NSAID) 通过抑制环氧合酶 (COX) 来阻断 PG 和血栓素，尽管它们具有众所周知的毒性，但仍用于治疗慢性疼痛和炎症。新的 NSAIDs 靶向 COXs 下游的一种酶，微粒体前列腺素 E 合酶 1 (mPGES-1)。抑制炎性巨噬细胞中的 mPGES-1 有望保留 NSAID 功效，同时限制毒性。我们将一种有效的 mPGES-1 抑制剂 MK-7285 与叶酸结合，但该构建体无法有效地释放药物。叶酸与 MK-7285 的伯醇结合提高了构建体的稳定性和游离药物的释放。令人惊讶的是，药物-叶酸偶联物增强了 FR 阳性 KB 细胞中的 PGE 2 并降低了_{PGE 2}在独立于 FR 的巨噬细胞中。非甾体抗炎药的叶酸结合不是靶向巨噬细胞的最佳策略。