Many cancer therapy regimes still rely heavily on the systemic administration of toxic chemotherapeutic agents. Ultrasound contrast agents consisting of microbubbles (MBs) have emerged as a drug delivery vehicle to overcome the challenges associated with systemic chemotherapy. Here, we describe the development of non-immunogenic, functionalized polylactic acid (PLA) MBs for use in targeted cancer therapy. Our previous studies have shown that the balance between acoustic behavior and improved immune avoidance was scalable and successful to different degrees with two different PEGylation methods and was best achieved using incorporation of PEG–PLA at 5 wt % and for a LipidPEG at 1 wt %. Capitalizing on this, we now attach a targeting ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which selectively induces tumor cell death upon binding to cancer cell-specific surface receptors, initiating a transmembrane apoptosis signal. Additionally, the functionalized MBs were designed to coencapsulate doxorubicin (Dox) that can be released from the polymer shell in response to ultrasound focused at the tumor site, shielding healthy tissues from toxicity while increasing the potency and efficiency of treatment to the tumor tissue. Ligation of TRAIL reduced the encapsulation efficiency for Dox compared to those of their non-ligated counterparts (p < 0.0001) by approximately 34% for 100% PLA, 23% for 5 wt % PEG–PLA, and 30% for the 1 wt % LipidPEG platform. All platforms exhibited a burst effect (<7%, p < 0.0001), and sustained release lasted for over 150 h. This work has resulted in a choice of effective ultrasound-triggered, non-immunogenic, targeted drug delivery agents for potential use in cancer therapy. These platforms have many advantages over the systemic administration of chemotherapeutic drugs and represent a promising treatment to better serve the population with solid cancerous tumors as a whole.

中文翻译：

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多面超声造影剂的药物输送：壳成分的影响

许多癌症治疗方案仍然严重依赖于毒性化学治疗剂的全身给药。由微泡（MBs）组成的超声造影剂已成为一种药物输送工具，可以克服与全身化学疗法相关的挑战。在这里，我们描述了非免疫原性，功能化的聚乳酸（PLA）MB的发展，用于靶向癌症治疗。我们以前的研究表明，通过两种不同的PEG化方法，声学行为和改善的免疫回避之间的平衡是可扩展的，并且在不同程度上取得了成功，并且最好是掺入5 wt％的PEG-PLA和1 wt％的LipidPEG。利用这一点，我们现在连接了靶向配体，肿瘤坏死因子相关的凋亡诱导配体（TRAIL），它在与癌细胞特异性表面受体结合后选择性诱导肿瘤细胞死亡，从而引发跨膜细胞凋亡信号。另外，功能化的MBs被设计为共封装阿霉素（Dox），该阿霉素可以响应于聚焦在肿瘤部位的超声而从聚合物外壳中释放出来，从而保护健康组织免受毒性，同时增加对肿瘤组织的治疗效力和效率。与未连接的TRAIL相比，TRAIL的连接降低了Dox的封装效率（保护健康组织免受毒性，同时增加对肿瘤组织的治疗效力和效率。与未连接的TRAIL相比，TRAIL的连接降低了Dox的封装效率（保护健康组织免受毒性，同时增加对肿瘤组织的治疗效力和效率。与未连接的TRAIL相比，TRAIL的连接降低了Dox的封装效率（p <0.0001）对于100％PLA约为34％，对于5 wt％PEG-PLA为23％，对于1 wt％LipidPEG平台为30％。所有平台均表现出爆发效应（<7％，p <0.0001），持续释放持续超过150小时。这项工作已导致选择有效的超声触发，非免疫原性，靶向药物递送剂，以潜在地用于癌症治疗。这些平台相对于化学治疗药物的全身给药具有许多优势，代表了一种有前途的治疗方法，可以更好地为整体患有实体癌的人群提供服务。