Netti P A, Hamberg L M, Babich J W, Kierstead D, Graham W, Hunter G J, Wolf G L, Fischman A, Boucher Y, Jain R K
Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Department of Radiology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA.
Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3137-42. doi: 10.1073/pnas.96.6.3137.
Cancer therapies using genes and other macromolecules might realize their full clinical potential if they could be delivered to tumor tissue in optimal quantities. Unfortunately, the compromised circulation within tumors poses a formidable resistance to adequate and uniform penetration of these agents. Previously, we have proposed elevated interstitial fluid pressure (IFP) as a major physiological barrier to delivery of macromolecules. Here we postulate that modulation of tumor microvascular pressure (MVP) and associated changes in IFP would enhance macromolecular delivery into a solid tumor. To test our hypothesis, we altered tumor MVP by either periodic injection or continuous infusion of angiotensin II (AII) and measured the resulting changes in IFP and uptake of macromolecules. We used the nicotinyl hydrazine derivative of human polyclonal IgG (HYNIC-IgG) as a nonspecific macromolecule and CC49 antibody as a specific macromolecule. We found that both chronic and periodic modulation of tumor MVP enhances transvascular fluid filtration, leading to a 40% increase in total uptake of the specific antibody within 4 hr of its administration. Conversely, neither continuous nor periodic infusion of AII induced any increase in uptake of nonspecific antibodies. Strategies to improve delivery of macromolecules and limitations of this approach are identified.
如果能够以最佳剂量将使用基因和其他大分子的癌症疗法输送到肿瘤组织中，那么它们可能会充分发挥其临床潜力。不幸的是，肿瘤内受损的循环对这些药物的充分和均匀渗透构成了巨大阻力。此前，我们曾提出升高的组织间液压力（IFP）是大分子输送的主要生理障碍。在此，我们假设调节肿瘤微血管压力（MVP）以及IFP的相关变化将增强大分子向实体瘤的输送。为了验证我们的假设，我们通过周期性注射或持续输注血管紧张素II（AII）来改变肿瘤MVP，并测量由此导致的IFP变化以及大分子的摄取情况。我们使用人多克隆IgG的烟酰肼衍生物（HYNIC-IgG）作为非特异性大分子，CC49抗体作为特异性大分子。我们发现，对肿瘤MVP的慢性和周期性调节均能增强跨血管液体滤过，导致特异性抗体在给药后4小时内的总摄取量增加40%。相反，持续或周期性输注AII均未引起非特异性抗体摄取量的增加。我们确定了改善大分子输送的策略以及该方法的局限性。
