Engineering and Validation of a Peptide-Stabilized Poly(lactic-co-glycolic) Acid Nanoparticle for Targeted Delivery of a Vascular Disruptive Agent in Cancer Therapy.
Engineering and Validation of a Peptide-Stabilized Poly(lactic-co-glycolic) Acid Nanoparticle for Targeted Delivery of a Vascular Disruptive Agent in Cancer Therapy.
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肽稳定聚（乳酸-羟基乙酸）酸纳米颗粒在肿瘤治疗中血管破坏剂靶向递送的工程和验证。
DOI：
10.1021/acs.bioconjchem.2c00418
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发表时间：
2022-12-21
影响因子：
4.7
通讯作者：
Mieszawska AJ
中科院分区：
文献类型：
--
作者：
Dragulska SA;Poursharifi M;Chen Y;Wlodarczyk MT;Acosta Santiago M;Dottino P;Martignetti JA;Mieszawska AJ
开发一种生物相容性和生物可降解的纳米颗粒（NP）载体，整合药物负载能力，主动靶向和成像模式是极具挑战性的。在此，我们报告了一种具有聚（乳酸-乙醇酸）（PLGA）核心的NP，该NP用药物考布他汀-A4（CA 4）进行化学修饰，考布他汀-A4是一种血管破坏剂（VDA），正在临床开发用于卵巢癌（OvCA）治疗。通过肽在PLGA表面上的自组装，用短的甘氨酸-甘氨酸-天冬氨酸-苯丙氨酸x3（RGDFFF）肽稳定NP。重要的是，我们的RGDFFF涂层的使用取代了常用的聚乙二醇（PEG）聚合物，其本身经常诱导不需要的免疫原性应答。此外，众所周知，肽的RGD基序优先结合αvβ3整联蛋白，αvβ3整联蛋白与肿瘤血管生成有关，并被用作NP的靶向组分。通过PLGA的化学修饰，用光学成像荧光团标记增强NP。RGDFF-CA 4 NP使用纳米沉淀法合成，直径约为75 ± 3.7 nm，其中肽涂层包含2-3 nm外层。NP在血清中稳定72小时。使用人脐带血管内皮细胞（HUVEC）的体外研究证实了RGDFF-CA 4 NP的高摄取和生物活性。在培养物中生长的OvCA细胞中证明了NP摄取和活力降低，并且NP在临床前OvCA小鼠模型中有效地积累在肿瘤中。当与免疫细胞一起培养时，RGDFFF NP不诱导炎症反应。最后，NP被患者来源的OvCA细胞有效地摄取，这表明了未来临床应用的潜力。
Developing a biocompatible and biodegradable nanoparticle (NP) carrier that integrates drug-loading capability, active targeting, and imaging modality is extremely challenging. Herein, we report a NP with a core of poly(lactic-co-glycolic) acid (PLGA) chemically modified with a drug combretastatin-A4 (CA4), a vascular disrupting agent (VDA) in clinical development for ovarian cancer (OvCA) therapy. The NP is stabilized with a short arginine-glycine-aspartic acid-phenylalanine x3 (RGDFFF) peptide via self-assembly of the peptide on the PLGA surface. Importantly, the use of our RGDFFF coating replaces commonly used polyethylene glycol (PEG) polymer which itself often induces an unwanted immunogenic response. In addition, the RGD motif of the peptide is well-known to preferentially bind to αvβ3 integrin which is implicated in tumor angiogenesis and is exploited as the NP’s targeting component. The NP is enhanced with an optical imaging fluorophore label via chemical modification of the PLGA. The RGDFFF-CA4 NPs are synthesized using a nanoprecipitation method and are ~75 ± 3.7 nm in diameter, where a peptide coating comprises a 2–3 nm outer layer. The NPs are serum stable for 72 h. In vitro studies using human umbilical cord vascular endothelial cells (HUVEC) confirmed high uptake and biological activity of the RGDFFF-CA4 NP. NP uptake and viability reduction were demonstrated in OvCA cells grown in culture and the NPs efficiently accumulated in tumors in a preclinical OvCA mouse model. The RGDFFF NP did not induce an inflammatory response when cultured with immune cells. Finally, the NP was efficiently taken up by patient-derived OvCA cells suggesting a potential for future clinical applications.
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DOI：
10.3390/molecules23092157
发表时间：
2018-08-27
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Ahlawat J;Henriquez G;Narayan M
通讯作者：
Narayan M
影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
影响因子：
3
作者：
Cheetham AG;Keith D;Zhang P;Lin R;Su H;Cui H
通讯作者：
Cui H
影响因子：
2.7
作者：
Gamble LJ;Borovjagin AV;Matthews QL
通讯作者：
Matthews QL
影响因子：
3.2
作者：
Eltabbakh, G H;Awtrey, C S
通讯作者：
Awtrey, C S