Poly(2-oxazoline) nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving CNS pharmacokinetics and reducing systemic toxicity.
Poly(2-oxazoline) nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving CNS pharmacokinetics and reducing systemic toxicity.
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DOI：
10.1016/j.nano.2020.102345
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Sokolsky-Papkov PhD M
中科院分区：
文献类型：
--
作者：
Hwang D;Dismuke T;Tikunov A;Rosen EP;Kagel JR;Ramsey JD;Lim C;Zamboni W;Kabanov AV;Gershon TR;Sokolsky-Papkov PhD M
我们报告了一种SHH途径抑制剂vismodegib的纳米制剂，它可以提高髓母细胞瘤的疗效，同时降低毒性。有限的血脑屏障(BBB)穿透和剂量限制的神经外毒性使脑肿瘤的全身治疗变得复杂。Vismodegib被FDA批准用于SHH驱动的基底细胞癌，但由于疗效不足和过度的骨毒性，对髓母细胞瘤的实施一直受到限制。为了通过优化药物输送来解决这些问题，我们在聚恶唑啉嵌段共聚胶束中配制了vismodegib(POX-VISMO)。然后，我们在发生SHH驱动的髓母细胞瘤的转基因小鼠中评估了POX-VISMO，这些小鼠具有天然的血管系统和肿瘤微环境。POX-VISMO改善了中枢神经系统的药代动力学，并降低了骨毒性。从机制上讲，纳米颗粒载体没有进入中枢神经系统，而是在血管腔内发挥作用，改善药物的输送。与传统的vismodegib不同，POX-VISMO延长了带髓母细胞瘤小鼠的存活时间。我们的结果表明，非靶向纳米颗粒制剂在改善全身性脑肿瘤治疗方面具有广阔的潜力，特别是在改善SHH驱动的癌症的Vismodegib治疗方面。
We report a nanoparticle formulation of the SHH-pathway inhibitor vismodegib that improves efficacy for medulloblastoma, while reducing toxicity. Limited blood–brain barrier (BBB) penetration and dose-limiting extraneural toxicities complicate systemic therapies for brain tumors. Vismodegib is FDA-approved for SHH-driven basal cell carcinoma, but implementation for medulloblastoma has been limited by inadequate efficacy and excessive bone toxicity. To address these issues through optimized drug delivery, we formulated vismodegib in polyoxazoline block copolymer micelles (POx-vismo). We then evaluated POx-vismo in transgenic mice that develop SHH-driven medulloblastomas with native vasculature and tumor microenvironment. POx-vismo improved CNS pharmacokinetics and reduced bone toxicity. Mechanistically, the nanoparticle carrier did not enter the CNS, and acted within the vascular compartment to improve drug delivery. Unlike conventional vismodegib, POx-vismo extended survival in medulloblastoma-bearing mice. Our results show the broad potential for non-targeted nanoparticle formulation to improve systemic brain tumor therapy, and specifically to improve vismodegib therapy for SHH-driven cancers.
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影响因子：
16.1
作者：
Hwang D;Ramsey JD;Kabanov AV
通讯作者：
Kabanov AV
影响因子：
14
作者：
He, Zhijian;Wan, Xiaomeng;Schulz, Anita;Bludau, Herdis;Dobrovolskaia, Marina A.;Stern, Stephan T.;Montgomery, Stephanie A.;Yuan, Hong;Li, Zibo;Alakhova, Dania;Sokolsky, Marina;Darr, David B.;Perou, Charles M.;Jordan, Rainer;Luxenhofer, Robert;Kabanov, Alexander V.
通讯作者：
Kabanov, Alexander V.
DOI：
10.1007/978-1-60327-198-1_6
发表时间：
2011-01-01
期刊：
CHARACTERIZATION OF NANOPARTICLES INTENDED FOR DRUG DELIVERY
影响因子：
--
作者：
Clogston, Jeffrey D.;Patri, Anil K.
通讯作者：
Patri, Anil K.
影响因子：
4.6
作者：
Lang, Patrick Y.;Nanjangud, Gouri J.;Gershon, Timothy R.
通讯作者：
Gershon, Timothy R.
DOI：
10.1016/j.nano.2017.06.004
发表时间：
2017-10
期刊：
Nanomedicine : nanotechnology, biology, and medicine
影响因子：
--
作者：
Kievit FM;Wang K;Ozawa T;Tarudji AW;Silber JR;Holland EC;Ellenbogen RG;Zhang M
通讯作者：
Zhang M