Increased microvascular permeability contributes to preferential accumulation of Stealth liposomes in tumor tissue.
Increased microvascular permeability contributes to preferential accumulation of Stealth liposomes in tumor tissue.
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发表时间：
1993-08
期刊：
影响因子：
11.2
通讯作者：
Ning Z. Wu;Daphne Da;Tracy L. Rudoll;David Needham;A. Whorton;M. Dewhirst
中科院分区：
文献类型：
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作者：
Ning Z. Wu;Daphne Da;Tracy L. Rudoll;David Needham;A. Whorton;M. Dewhirst
隐身脂质体作为一种很有前景的抗肿瘤药物传递系统，近年来尚无研究报道其在微循环水平上的动态行为。在本研究中，我们使用活体荧光视频显微镜研究了肿瘤和肉芽组织微循环制剂中隐形脂质体和常规脂质体的血浆浓度衰减和间质积累。将荧光标记的隐形脂质体或常规脂质体静脉注射到携带背侧鳞片窗腔的大鼠中，其中一些含有血管化的乳腺腺癌。注射后，随时间测量血管和间质内脂质体产生的荧光强度。这些测量结果用于推导肿瘤和肉芽化正常组织中每种脂质体的血浆药代动力学和血管通透性系数。注射后90分钟内，隐形脂质体在肿瘤间质中的积累量是常规脂质体的3-4倍。在90分钟结束时，给药脂质体在循环中保留的百分比为隐形脂质体的60.2%和常规脂质体的20.4%。隐形脂质体的肿瘤血管通透性为3.42 +/- 0.78 × 10(-7)cm/s，常规脂质体为1.75 × 0.38 × 10(-7)cm/s。在正常的肉芽组织中，两种结构的通透性在0.8-0.9 x 10(-7)cm/s时相等。总之，与常规脂质体相比，隐身脂质体在肿瘤中的优先积累可归因于较慢的血浆清除率和较高的血管通透性。我们将体内显微镜与肿瘤微循环模型相结合的方法为定量研究脂质体向肿瘤组织的传递提供了一种独特的方法，因为它可以用于在微循环水平上实时研究这一过程。
Stealth liposomes have recently emerged as a promising antitumor drug delivery system, yet no studies have been reported to examine their dynamic behavior at the microcirculatory level. In this investigation, we have used in vivo fluorescence videomicroscopy to study the decay in plasma concentration and the interstitial accumulation of Stealth and conventional liposomes in tumor and granulating tissue microcirculatory preparations. Fluorescently labeled Stealth or conventional liposomes were injected i.v. into rats bearing dorsal skinflap window chambers, some of which contained a vascularized mammary adenocarcinoma. After injection, fluorescent light intensities arising from liposomes within blood vessels and the interstitium were measured over time. These measurements were used to derive plasma pharmacokinetics and vascular permeability coefficients for each liposome species in both tumor and granulating normal tissues. Within the first 90 min after injection, Stealth liposome accumulation in the tumor interstitium was 3-4-fold that for conventional liposomes. The percentage of administered liposomes remaining in the circulation at the end of 90 min was 60.2% for Stealth and 20.4% for conventional liposomes. Tumor vascular permeability was 3.42 +/- 0.78 x 10(-7)cm/s for Stealth and 1.75 x 0.38 x 10(-7)cm/s for conventional liposomes. In normal granulating tissues permeability for the 2 constructs was equivalent at 0.8-0.9 x 10(-7)cm/s. In conclusion, preferential accumulation of Stealth liposomes in tumors was attributable to a combination of slower plasma clearance and higher vascular permeability relative to conventional liposomes. Our method of combining in vivo microscopy with a tumor microcirculatory model provides a unique approach to study quantitatively the delivery of liposomes to tumor tissues, since it can be used to study the process in real time at the microcirculatory level.