Macrophage depletion increases target specificity of bone-targeted nanoparticles.
Macrophage depletion increases target specificity of bone-targeted nanoparticles.
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DOI：
10.1002/jbm.a.37279
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Benoit DSW
中科院分区：
文献类型：
--
作者：
Ackun-Farmmer MA;Xiao B;Newman MR;Benoit DSW
尽管努力实现组织选择性，但大多数全身给药的药物递送系统（DDS）在到达靶组织之前被单核吞噬细胞系统（MPS）清除，而不管疾病/损伤病理学如何。之前，我们表明，虽然与对照组相比，抗酒石酸盐酸性磷酸酶（TRAP）结合肽（TBP）靶向聚合物纳米颗粒（TBP-NP）递送骨再生Wnt激动剂改善了NP骨折累积并加速愈合，但也存在显著的MPS累积。在此，我们发现TBP-NP被肝、脾、肺和骨髓巨噬细胞摄取，其中76 ± 4%、49 ± 11%、27 ± 9%和92 ± 5%的组织特异性巨噬细胞对NP呈阳性。氯膦酸盐脂质体（CLO）显著消耗肝脏和脾脏M β，导致肝脏和脾脏降低1.8倍和3倍，骨折增加1.3倍和1.6倍，以及TBP-NP的原始股骨蓄积。有趣的是，消耗和饱和也导致肺和肾中TBP-NP累积显著更高，可能通过代偿清除机制。10倍高的NP剂量导致在幼稚骨组织中更大的TBP-NP积累，然而，其他MPS组织（即，心脏和肺）表现出更大的TBP-NP积累，表明被其他细胞类型摄取。最重要的是，M β耗竭或饱和策略均未改善TBP-NP的断裂部位选择性，这可能是由于M β衍生的破骨细胞减少，其存款TRAP表位。总之，这些数据支持MPS介导的清除是全身给予骨靶向DDS的稳健和选择性骨折累积的关键障碍，并促使开发更复杂的方法以进一步提高DDS的骨折选择性。
Despite efforts to achieve tissue selectivity, the majority of systemically administered drug delivery systems (DDSs) are cleared by the mononuclear phagocyte system (MPS) before reaching target tissues regardless of disease/injury pathology. Previously, we showed that while tartrate-resistant acid phosphatase (TRAP) binding peptide (TBP)-targeted polymeric nanoparticles (TBP-NP) delivering a bone regenerative Wnt agonist improved NP fracture accumulation and expedited healing compared to controls, there was also significant MPS accumulation. Here we show that TBP-NPs are taken up by liver, spleen, lung, and bone marrow macrophages Mϕ), with 76 ± 4%, 49 ± 11%, 27 ± 9%, and 92 ± 5% of tissue-specific Mϕ positive for NP. Clodronate liposomes (CLO) significantly depleted liver and spleen Mϕ, resulting in 1.8- and 3-fold lower liver and spleen and 1.3-and 1.6-fold greater fracture and naïve femur accumulation of TBP-NP. Interestingly, depletion and saturation also resulted in significantly higher TBP-NP accumulation at lungs and kidneys potentially through compensatory clearance mechanisms. A 10-fold higher NP dose resulted in greater TBP-NP accumulation at naïve bone tissue however, other MPS tissues (i.e., heart and lungs) exhibited greater TBP-NP accumulation, suggesting uptake by other cell types. Most importantly, neither Mϕ depletion nor saturation strategies improved fracture site selectivity of TBP-NPs possibly due to a reduction of Mϕ-derived osteoclasts, which deposit the TRAP epitope. Altogether, these data support that MPS-mediated clearance is a key obstacle in robust and selective fracture accumulation for systemically administered bone-targeted DDS and motivates the development of more sophisticated approaches to further improve fracture selectivity of DDS.
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DOI：
10.1002/jor.23440
发表时间：
2017-08
期刊：
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
影响因子：
--
作者：
Lin HN;O'Connor JP
通讯作者：
O'Connor JP
影响因子：
6
作者：
Hao J;Han T;Wang M;Zhuang Q;Wang X;Liu J;Wang Y;Tang H
通讯作者：
Tang H
靶向骨折的GSK3β抑制剂胶束的生物分布可改善断裂愈合。
影响因子：
6.2
作者：
Low SA;Galliford CV;Yang J;Low PS;Kopeček J
通讯作者：
Kopeček J
DOI：
10.1096/fj.202000938rr
发表时间：
2021-04
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Ackun-Farmmer MA;Soto CA;Lesch ML;Byun D;Yang L;Calvi LM;Benoit DSW;Frisch BJ
通讯作者：
Frisch BJ
影响因子：
17.4
作者：
Liu, Ting;Choi, Hoon;Chen, I-Wei
通讯作者：
Chen, I-Wei