Evaluation of pharmacokinetic and pharmacodynamic profiles of liposomes for the cell type-specific delivery of small molecule drugs.
Evaluation of pharmacokinetic and pharmacodynamic profiles of liposomes for the cell type-specific delivery of small molecule drugs.
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DOI：
10.1016/j.nano.2017.07.005
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Kelly KA
中科院分区：
文献类型：
--
作者：
Dasa SSK;Suzuki R;Mugler E;Chen L;Jansson-Löfmark R;Michaëlsson E;Lindfors L;Klibanov AL;French BA;Kelly KA
基于脂质体的药物制剂代表了一个令人兴奋的研究途径，因为它们增加了功效与毒性的比率。目前的制剂依赖于被动积累到疾病部位，其中药物被细胞吸收。配体介导的靶向增加了脂质体的净积累，然而，一个尚未探索的好处是可能改善药物针对患病组织内不同细胞类型的药效学（PD）。作为模型系统，我们设计了心肌细胞（I-1）和内皮细胞（B-40）靶向脂质体，以携带VEGFR 2抑制剂（PTK 787），并检查了细胞类型特异性递送对药代动力学（PK）和PD的影响。与注射I-1脂质体的动物相比，负载PTK 787的B-40脂质体显著降低了心肌梗死后的新血管形成，与游离PTK 787相比，其程度更深。因此，该研究表明，通过细胞类型特异性递送的药物的器官内靶向具有降低全身给药的最小有效剂量的实质性希望。心脏再生的复杂性使其成为确定脂质体的细胞类型特异性靶向是否会影响药效学和解剖学终点的严格模型系统。使用心肌缺血/再灌注损伤的小鼠模型和先前鉴定的靶向心肌细胞或内皮的肽，我们在这里证明，与靶向心肌细胞的脂质体或游离药物相比，靶向内皮的脂质体可以显著改变体内药效学和生理学终点。这项工作首次证明了梗死后心脏内小分子药物的差异细胞类型靶向可以左移剂量反应曲线，从而降低有效剂量。
Liposome-based drug formulations represent an exciting avenue of research as they increase efficacy to toxicity ratios. Current formulations rely on passive accumulation to the disease site where drug is taken up by the cells. Ligand mediated targeting increases the net accumulation of liposomes, however, an unexplored benefit is to potentially refine pharmacodynamics (PD) of a drug specifically to different cell types within diseased tissue. As a model system, we engineered cardiomyocyte- (I-1) and endothelial-targeted (B-40) liposomes to carry a VEGFR2 inhibitor (PTK787), and examined the effect of cell type-specific delivery on both pharmacokinetics (PK) and PD. Neovascularization in post-myocardial infarction was significantly reduced by B-40 liposomes loaded with PTK787 as compared to animals injected with I-1 liposomes, and profoundly more as compared to free PTK787. This study thus shows that the intraorgan targeting of drugs through cell type-specific delivery holds substantial promise towards lowering the minimal efficacious dose administered systemically. The complexities of cardiac regeneration make it a stringent model system for determining whether cell type-specific targeting of liposomes can affect pharmacodynamic and anatomic endpoints. Using a mouse model of myocardial ischemia/reperfusion injury and previously identified peptides targeting either cardiomyocytes or endothelium, we demonstrate here that endothelial-targeted liposomes can significantly alter pharmacodynamic and physiological endpoints in vivo as compared to cardiomyocyte-targeted liposomes or free drug. This work demonstrates for the first time that differential cell type-targeting of a small molecule drug within the post-infarct heart can left-shift the dose-response curve, thus reducing the efficacious dose.
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影响因子：
17.1
作者：
Kunjachan S;Gremse F;Theek B;Koczera P;Pola R;Pechar M;Etrych T;Ulbrich K;Storm G;Kiessling F;Lammers T
通讯作者：
Lammers T
影响因子：
8
作者：
Bozzuto G;Molinari A
通讯作者：
Molinari A
影响因子：
5.4
作者：
Nag OK;Awasthi V
通讯作者：
Awasthi V
DOI：
10.1016/j.jconrel.2015.06.017
发表时间：
2015-12-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Dasa SSK;Suzuki R;Gutknecht M;Brinton LT;Tian Y;Michaelsson E;Lindfors L;Klibanov AL;French BA;Kelly KA
通讯作者：
Kelly KA
影响因子：
5.6
作者：
Sercombe L;Veerati T;Moheimani F;Wu SY;Sood AK;Hua S
通讯作者：
Hua S