Adjei Isaac M, Sharma Blanka, Peetla Chiranjeevi, Labhasetwar Vinod
Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
J Control Release. 2016 Jun 28;232:83-92. doi: 10.1016/j.jconrel.2016.04.019. Epub 2016 Apr 15.
Advanced-stage prostate cancer usually metastasizes to bone and is untreatable due to poor biodistribution of intravenously administered anticancer drugs to bone. In this study, we modulated the surface charge/composition of biodegradable nanoparticles (NPs) to sustain their blood circulation time and made them small enough to extravasate through the openings of the bone's sinusoidal capillaries and thus localize into marrow. NPs with a neutral surface charge, achieved by modulating the NP surface-associated emulsifier composition, were more effective at localizing to bone marrow than NPs with a cationic or anionic surface charge. These small neutral NPs (~150nm vs. the more usual ~320nm) were also ~7-fold more effective in localizing in bone marrow than large NPs. We hypothesized that NPs that effectively localize to marrow could improve NP-mediated anticancer drug delivery to sites of bone metastasis, thereby inhibiting cancer progression and preventing bone loss. In a PC-3M-luc cell-induced osteolytic intraosseous model of prostate cancer, these small neutral NPs demonstrated greater accumulation in bone within metastatic sites than in normal contralateral bone as well as co-localization with the tumor mass in marrow. Significantly, a single-dose intravenous administration of these small neutral NPs loaded with paclitaxel (PTX-NPs), but not anionic PTX-NPs, slowed the progression of bone metastasis. In addition, neutral PTX-NPs prevented bone loss, whereas animals treated with the rapid-release drug formulation Cremophor EL (PTX-CrEL) or saline (control) showed >50% bone loss. Neutral PTX-NPs did not cause acute toxicity, whereas animals treated with PTX-CrEL experienced weight loss. These results indicate that NPs with appropriate physical and sustained drug-release characteristics could be explored to treat bone metastasis, a significant clinical issue in prostate and other cancers.
晚期前列腺癌通常会转移至骨骼，由于静脉注射的抗癌药物在骨骼中的生物分布不佳，因此无法治疗。在本研究中，我们调节了可生物降解纳米颗粒（NPs）的表面电荷/组成，以延长其血液循环时间，并使其足够小，能够通过骨髓窦状毛细血管的开口渗出，从而定位于骨髓中。通过调节NP表面相关乳化剂组成实现的具有中性表面电荷的NPs，比具有阳离子或阴离子表面电荷的NPs在定位于骨髓方面更有效。这些小的中性NPs（约150nm，而通常为约320nm）在定位于骨髓方面也比大的NPs有效约7倍。我们假设，有效定位于骨髓的NPs可以改善NP介导的抗癌药物向骨转移部位的递送，从而抑制癌症进展并预防骨质流失。在PC-3M-luc细胞诱导的前列腺癌溶骨性骨内模型中，这些小的中性NPs在转移部位的骨骼中比在对侧正常骨骼中积累更多，并且与骨髓中的肿瘤块共定位。值得注意的是，单剂量静脉注射这些负载紫杉醇的小中性NPs（PTX-NPs），而不是阴离子PTX-NPs，减缓了骨转移的进展。此外，中性PTX-NPs预防了骨质流失，而用速释药物制剂聚氧乙烯蓖麻油（PTX-CrEL）或生理盐水（对照）治疗的动物显示骨质流失>50%。中性PTX-NPs未引起急性毒性，而用PTX-CrEL治疗的动物体重减轻。这些结果表明，可以探索具有适当物理特性和持续药物释放特性的NPs来治疗骨转移，这是前列腺癌和其他癌症中的一个重要临床问题。
