Advancing Bone-Targeted Drug Delivery: Leveraging Biological Factors and Nanoparticle Designs to Improve Therapeutic Efficacy
Advancing Bone-Targeted Drug Delivery: Leveraging Biological Factors and Nanoparticle Designs to Improve Therapeutic Efficacy
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DOI：
10.1021/acsbiomaterials.3c01022
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发表时间：
2024-03-27
影响因子：
5.8
通讯作者：
Benoit，Danielle S. W.
中科院分区：
文献类型：
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作者：
Xiao，Baixue;Ackun-Farmmer，Marian A.;Benoit，Danielle S. W.
设计靶向给药系统以有效治疗从骨质疏松症到骨不连的骨缺损的骨疾病仍然是一个重大的挑战。先前，由聚（苯乙烯-alt-马来酸酐）-b-聚（苯乙烯）（PSMA-b-PS）的二嵌段共聚物自组装的纳米颗粒（NP）递送Wnt激动剂，通过引入对抗酒石酸酸性磷酸酶（TRAP）具有高亲和力的肽（一种在骨重建期间由破骨细胞沉积的酶），可有效靶向骨并改善愈合。尽管有这些有希望的结果，潜在的生物学因素控制的目标和随后的药物输送系统（DDS）的设计参数尚未进行检查，使合理的设计，以提高骨的选择性。因此，这项工作研究了靶配体密度、损伤后的治疗窗口、TRAP结合肽（TBP）的特异性、TRAP沉积的程度和潜在的遗传因素（例如，小鼠品系差异）对TBP-NP靶向的影响。基于体外结合研究和使用小鼠股骨骨折模型的体内生物分布分析的数据表明，TBP-NP-TRAP相互作用和TBP-NP骨蓄积是配体密度依赖性的;在体外，TRAP亲和力与配体密度相关，最高达200，000个TBP配体/NP，而具有80，000个TBP配体在损伤后第21天显示与未靶向或乱序对照相比骨折累积增加2倍。虽然与骨折后第21天相比，在第3天注射时骨折累积表现出类似的趋势，但在TBP官能化的NP和对照NP之间没有观察到显著差异，这可能是由于在第3天NP对TRAP的饱和。利用钙消耗饮食，TRAP沉积和TBP-NP骨积累呈正相关，证实TRAP-TBP结合导致体内TBP-NP骨积累。此外，TBP-NP在C57 BL/6和BALB/c小鼠品系中与对照NP表现出相似的骨积累，表明TBP-NP的广泛适用性，而不管潜在的遗传差异。这些研究提供了对TBP-NP设计、机制和治疗窗口的深入了解，为骨折和其他利用TRAP的骨相关疾病（如骨髓相关血液病）的NP设计和治疗策略提供了信息。
Designing targeted drug delivery systems to effectively treat bone diseases ranging from osteoporosis to nonunion bone defects remains a significant challenge. Previously, nanoparticles (NPs) self-assembled from diblock copolymers of poly(styrene-alt-maleic anhydride)-b-poly(styrene) (PSMA-b-PS) delivering a Wnt agonist were shown to effectively target bone and improve healing via the introduction of a peptide with high affinity to tartrate-resistant acid phosphatase (TRAP), an enzyme deposited by the osteoclasts during bone remodeling. Despite these promising results, the underlying biological factors governing targeting and subsequent drug delivery system (DDS) design parameters have not been examined to enable the rational design to improve bone selectivity. Therefore, this work investigated the effect of target ligand density, the treatment window after injury, specificity of TRAP binding peptide (TBP), the extent of TRAP deposition, and underlying genetic factors (e.g., mouse strain differences) on TBP-NP targeting. Data based on in vitro binding studies and in vivo biodistribution analyses using a murine femoral fracture model suggest that TBP-NP-TRAP interactions and TBP-NP bone accumulation were ligand-density-dependent; in vitro, TRAP affinity was correlated with ligand density up to the maximum of 200,000 TBP ligands/NP, while NPs with 80,000 TBP ligands showed 2-fold increase in fracture accumulation at day 21 post injury compared with that of untargeted or scrambled controls. While fracture accumulation exhibited similar trends when injected at day 3 compared to that at day 21 postfracture, there were no significant differences observed between TBP-functionalized and control NPs, possibly due to saturation of TRAP by NPs at day 3. Leveraging a calcium-depletion diet, TRAP deposition and TBP-NP bone accumulation were positively correlated, confirming that TRAP-TBP binding leads to TBP-NP bone accumulation in vivo. Furthermore, TBP-NP exhibited similar bone accumulation in both C57BL/6 and BALB/c mouse strains versus control NPs, suggesting the broad applicability of TBP-NP regardless of the underlying genetic differences. These studies provide insight into TBP-NP design, mechanism, and therapeutic windows, which inform NP design and treatment strategies for fractures and other bone-associated diseases that leverage TRAP, such as marrow-related hematologic diseases.