One of the greatest challenges in cancer therapy is to control metastatic spread, seeding, and growth of tumors in distant organs. Recently, we reported on the design of a novel “drug-free” therapeutic copolymer bearing the antimigratory A5G27 peptide, designated P-(A5G27)-FITC, that shows excellent specificity to cancer cells overexpressing CD44v3 and CD44v6 and inhibits cancer cell migration and invasion. We demonstrated that P-(A5G27)-FITC accumulated preferentially in subcutaneous (sc) implanted 4T1 tumors following parenteral administration. Moreover, we showed that pretreatment of mice with P-(A5G27)-FITC prior to 4T1 cell inoculation inhibited colonization of circulating 4T1 cells in the lungs. In this study, we designed a new polymer-peptide-drug conjugate to inhibit vigorously growing primary tumors and control invasive behavior of cancer cells. To this end, the antimitotic drug (paclitaxel, PTX) was conjugated to P-(A5G27)-FITC. The targeted polymer–drug conjugate (P-(A5G27)-PTX) was significantly more toxic toward CD44-overexpressing cancer cells than the nontargeted copolymer. In vivo, a single iv injection of P-(A5G27)-PTX prolonged the survival of C57BL/6 mice with established B16-F10 lung metastases. When injected intraperitoneally into BALB/c mice implanted sc with 4T1 tumors, P-(A5G27)-PTX significantly decreased the rate of primary tumor growth, increased the median survival of mice, and reduced the number of 4T1 metastases in the lungs when compared to nontargeted copolymer. Most interestingly, the CD44-targeted “drug-free” copolymer P-(A5G27) (without PTX) significantly inhibited the rate of tumor growth and further prolonged the median survival time of mice to the same extent as the PTX-containing formulations (P-(A5G27)-PTX or free PTX). Overall, this study highlights the therapeutic potential of the HPMA copolymer–A5G27 conjugates (“drug-free” and PTX-bearing copolymers) to control the metastatic spread of cancer.

中文翻译：

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靶向CD44的聚合物-紫杉醇可控制转移性肿瘤的扩散和生长。

癌症治疗中的最大挑战之一是控制远处器官中肿瘤的转移扩散，播种和生长。最近，我们报道了带有抗迁移性A5G27肽（称为P-（A5G27）-FITC）的新型“无药”治疗性共聚物的设计，该共聚物对过表达CD44v3和CD44v6的癌细胞表现出优异的特异性，并抑制癌细胞的迁移和侵袭。我们证明了肠胃外给药后，P-（A5G27）-FITC在皮下（sc）植入的4T1肿瘤中优先积累。此外，我们显示在接种4T1细胞之前用P-（A5G27）-FITC进行的小鼠预处理抑制了循环中的4T1细胞在肺中的定殖。在这项研究中，我们设计了一种新的聚合物-肽-药物结合物，以抑制旺盛生长的原发肿瘤并控制癌细胞的侵袭行为。为此，将抗有丝分裂药物（紫杉醇，PTX）缀合至P-（A5G27）-FITC。靶向的药物-药物结合物（P-（A5G27）-PTX）对CD44过表达的癌细胞的毒性要比非靶向的共聚物高得多。在体内，单次静脉内注射P-（A5G27）-PTX可延长具有已建立的B16-F10肺转移的C57BL / 6小鼠的生存期。当与经皮下植入4T1肿瘤的BALB / c小鼠腹膜内注射时，与非目标共聚物。最有趣的是 靶向CD44的“无药”共聚物P-（A5G27）（不含PTX）显着抑制肿瘤的生长速度，并进一步延长了小鼠的中位生存时间，达到了与含PTX制剂相同的程度（P-（A5G27 ）-PTX或免费的PTX）。总体而言，这项研究强调了HPMA共聚物-A5G27共轭物（“无药”和带有PTX的共聚物）在控制癌症转移扩散方面的治疗潜力。