Biomedical Engineering Center, Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, E25-438, Cambridge, Massachusetts 02139, USA.
J Control Release. 2009 Jun 5;136(2):99-109. doi: 10.1016/j.jconrel.2009.01.016. Epub 2009 Feb 3.
Dynamic architecture and motion in mechanically active target tissues can influence the pharmacokinetics of locally delivered agents. Drug transport in skeletal muscle under controlled mechanical loads was investigated. Static (0-20%) and cyclic (+/-2.5% amplitude, 0-20% mean, 1-3 Hz) strains and electrically paced isometric contractions (0.1-3 Hz, 0% strain) were applied to rat soleus incubated in 1 mM 20 kDa FITC-dextran. Dextran penetration, tissue porosity, and active force-length relationship over 0-20% strain correlated (r=0.9-1.0), and all increased 1.5-fold from baseline at 0% to a maximum at 10% (Lo), demonstrating biologic significance of Lo and impact of fiber size and distribution on function and pharmacokinetics. Overall penetration decreased but relative enhancement of penetration at Lo increased with dextran size (4-150 kDa). Penetration increased linearly (0.084 mm/Hz) with cyclic stretch, demonstrating dispersion. Penetration increased with contraction rate by 1.5-fold from baseline to a maximum at 0.5 Hz, revealing architectural modulation of dispersion. Impact of architecture and dispersion on intramuscular transport was computationally modeled. Mechanical architecture and function underlie intramuscular pharmacokinetics and act in concert to effect resonance between optimal physiologic performance and drug uptake. Therapeutic management of characteristic function in tissue targets may enable a physiologic mechanism for controlled drug transport.
机械活跃靶组织中的动态结构和运动可影响局部递送药物的药代动力学。研究了在受控机械负荷下骨骼肌中的药物输送。静态（0-20%）和循环（+/-2.5%幅度，0-20%平均值，1-3 Hz）应变以及电刺激等长收缩（0.1-3 Hz，0%应变）应用于在 1 mM 20 kDa FITC-葡聚糖孵育的大鼠比目鱼肌。葡聚糖渗透、组织孔隙率和 0-20%应变下的主动力-长度关系相关（r=0.9-1.0），并且在 0%至 10%（Lo）时，所有值均从基线增加 1.5 倍，表明 Lo 的生物学意义以及纤维大小和分布对功能和药代动力学的影响。整体渗透减少，但相对 Lo 时的渗透增强随葡聚糖大小（4-150 kDa）而增加。渗透随循环拉伸线性增加（0.084 mm/Hz），表明分散。渗透随收缩率增加 1.5 倍，从基线增加至 0.5 Hz 时达到最大值，揭示了分散的结构调节。结构和分散对肌内转运的影响通过计算模型进行了研究。肌内药代动力学的基础是机械结构和功能，它们协同作用，在最佳生理性能和药物摄取之间产生共振。组织靶标中特征性功能的治疗管理可能为受控药物输送提供一种生理机制。
