Polyplexes are required to be equipped with multiple functionalities to accomplish adequate structure stability and gene transfection efficacy for gene therapy. Herein, a 4-carboxy-3-fluorophenylboronic acid (FPBA)-functionalized block copolymer of PEG-b-PAsp(DET/FBA) and PAsp(DET/FBA) (abbreviated as PB and HB) was synthesized and applied for engineering functional polyplex micelles (PMs) through ionic complexation with pDNA followed by strategic cross-linking with nordihydroguaiaretic acid (NDGA) in respect to the potential linkage of polyphenol and FPBA moieties. In relation to polyplex micelles void of cross-linking, the engineered multifunctional polyplex micelles (PBHBN-PMs) were determined to possess improved structural tolerability against the exchange reaction with charged species. Besides, the FPBA/NDGA cross-linking appeared to be selectively cleaved in the acidic endosomal compartments but not the neutral milieu. Furthermore, the PBHB-PMs with the optimal FPBA/NDGA cross-linking degree were identified to possess appreciable cellular uptake and endosomal escape activities, eliciting a significantly high level of gene expression relative to P-PMs and PB-PMs. Eventually, in vivo antitumor therapy by our proposed multifunctional PMs appeared to be capable of facilitating expression of the antiangiogenic genomic payloads (sFlt-1 pDNA) via systemic administration. The enriched antiangiogenic sFlt-1 in the tumors could silence the activities of angiogenic cytokines for the inhibited neo-vasculature and the suppressed growth of orthotopic 4T1 tumors. Of note, the persistent expression of the antiangiogenic sFlt-1 is also presumed to migrate into the blood circulation, thereby accounting for an overall antiangiogenic environment in preventing the potential pulmonary metastasis. Hence, our elaborated multifaceted PMs inspired fascinating potential as an intriguing gene delivery system for the treatment of clinical solid tumors and metastasis.

中文翻译：

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去甲二氢愈创木酸交联苯基硼酸功能化聚合胶束用于原位和转移性肿瘤的抗血管生成基因治疗


聚合复合物需要配备多种功能，以实现足够的结构稳定性和基因治疗的基因转染功效。本文合成了 PEG-b-PAsp(DET/FBA) 和 PAsp(DET/FBA)（简称 PB 和 HB）的 4-羧基-3-氟苯基硼酸（FPBA）功能化嵌段共聚物，并将其应用于工程功能通过与 pDNA 离子络合，然后与去甲二氢愈创木酸 (NDGA) 策略性交联，以实现多酚和 FPBA 部分的潜在连接，形成复合胶束 (PM)。相对于没有交联的聚合胶束，工程化的多功能聚合胶束（PBHBN-PM）被确定具有改进的结构耐受性，以抵抗与带电物质的交换反应。此外，FPBA/NDGA 交联似乎在酸性内体区室中被选择性裂解，但在中性环境中则不然。此外，具有最佳 FPBA/NDGA 交联度的 PBHB-PM 被认为具有明显的细胞摄取和内体逃逸活性，相对于 P-PM 和 PB-PM 引发显着高水平的基因表达。最终，我们提出的多功能 PM 的体内抗肿瘤治疗似乎能够通过全身给药促进抗血管生成基因组有效负载 (sFlt-1 pDNA) 的表达。肿瘤中富集的抗血管生成sFlt-1可以沉默血管生成细胞因子的活性，从而抑制新血管系统和原位4T1肿瘤的生长。 值得注意的是，抗血管生成 sFlt-1 的持续表达也被认为迁移到血液循环中，从而解释了预防潜在肺转移的整体抗血管生成环境。因此，我们精心设计的多方面 PM 激发了作为治疗临床实体瘤和转移的有趣基因传递系统的巨大潜力。