Extracellular matrix degrading enzyme with stroma-targeting peptides enhance the penetration of liposomes into tumors.
Extracellular matrix degrading enzyme with stroma-targeting peptides enhance the penetration of liposomes into tumors.
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DOI：
10.1016/j.jconrel.2022.11.007
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发表时间：
2022-11
期刊：
影响因子：
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通讯作者：
Mayumi Ikeda-Imafuku;Yongsheng Gao;Suyog Shaha;Lily Li-Wen Wang;Kyung Soo Park;Mayuka Nakajima;Omokolade Adebowale;S. Mitragotri
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文献类型：
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作者：
Mayumi Ikeda-Imafuku;Yongsheng Gao;Suyog Shaha;Lily Li-Wen Wang;Kyung Soo Park;Mayuka Nakajima;Omokolade Adebowale;S. Mitragotri
基于增强的渗透性和滞留效应，已经开发了各种抗肿瘤纳米药物。然而，肿瘤中致密的细胞外基质（ECM）仍然是纳米颗粒递送和积聚到肿瘤中的主要屏障。虽然ECM降解酶，如胶原酶、透明质酸酶和菠萝蛋白酶，已被用于促进纳米颗粒的积累，但目前非肿瘤特异性递送方法产生的严重副作用限制了其临床应用。在这里，我们报告菠萝蛋白酶通过其共价连接到具有肿瘤ECM靶向能力的透明质酸（HA）-肽缀合物靶向递送到肿瘤组织中。ECM靶向肽，IV型胶原蛋白结合肽（C4 BP），基于它们结合三阴性乳腺癌（4 T1 tumorex vivo）的冷冻切片的能力从六种候选肽中选择。与未修饰的HA相比，HA-C4 BP缀合物在静脉内施用后在携带4 T1的小鼠中显示出肿瘤积累的显著增加。我们进一步证明了菠萝蛋白酶缀合的C4 BP-HA（C4 BP-HA-Bro）的全身施用增强了脂质体阿霉素的抗肿瘤功效。C4 BP-HA-Bro减少了胶原纤维的数量和长度，并改善了肿瘤内阿霉素的分布。输注C4 BP-HA-Bro后未观察到输注反应。因此，C4 BP-HA为菠萝蛋白酶的有效和安全递送提供了潜力，以改善治疗剂的肿瘤内递送。
Various anti-tumor nanomedicines have been developed based on the enhanced permeability and retention effect. However, the dense extracellular matrix (ECM) in tumors remains a major barrier for the delivery and accumulation of nanoparticles into tumors. While ECM-degrading enzymes, such as collagenase, hyaluronidase, and bromelain, have been used to facilitate the accumulation of nanoparticles, serious side effects arising from the current non-tumor-specific delivery methods limit their clinical applications. Here, we report targeted delivery of bromelain into tumor tissues through its covalent attachment to a hyaluronic acid (HA)-peptide conjugate with tumor ECM targeting ability. The ECM targeting peptide, collagen type IV-binding peptide (C4BP), was chosen from six candidate-peptides based on their ability to bind to frozen sections of triple-negative breast cancer, 4T1 tumorex vivo. The HA- C4BP conjugate showed a significant increase in tumor accumulation in 4T1-bearing mice after intravenous administration compared to unmodified HA. We further demonstrated that the systemic administration of bromelain conjugated C4BP-HA (C4BP-HA-Bro) potentiates the anti-tumor efficacy of liposomal doxorubicin. C4BP-HA-Bro decreased the number and length of collagen fibers and improved the distribution of doxorubicin within the tumor. No infusion reaction was noted after delivery of C4BP-HA-Bro. C4BP-HA thus offers a potential for effective and safe delivery of bromelain for improved intratumoral delivery of therapeutics.