Kozlovskaya Veronika, Ducharme Maxwell, Dolmat Maksim, Omweri James M, Tekin Volkan, Lapi Suzanne E, Kharlampieva Eugenia
Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States.
Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States.
Biomacromolecules. 2023 Apr 10;24(4):1784-1797. doi: 10.1021/acs.biomac.2c01539. Epub 2023 Mar 16.
Radiolabeled drug nanocarriers that can be easily imaged positron emission tomography (PET) are highly significant as their outcome can be quantitatively PET-traced with high sensitivity. However, typical radiolabeling of most PET-guided theranostic vehicles utilizes modification with chelator ligands, which presents various challenges. In addition, unlike passive tumor targeting, specific targeting of drug delivery vehicles binding affinity to overexpressed cancer cell receptors is crucial to improve the theranostic delivery to tumors. Herein, we developed Zr-labeled triblock copolymer polymersomes of 60 nm size through chelator-free radiolabeling. The polymersomes are assembled from poly(-vinylpyrrolidone)--poly(dimethylsiloxane)--poly(-vinylpyrrolidone) (PVPON-PDMS-PVPON) triblock copolymers followed by adsorption of a degradable tannin, tannic acid (TA), on the polymersome surface through hydrogen bonding. TA serves as an anchoring layer for both Zr radionuclide and targeting recombinant humanized monoclonal antibody, trastuzumab (Tmab). Unlike bare PVPON-PDMS-PVPON polymersomes, TA- and Tmab-modified polymersomes demonstrated a high radiochemical yield of more than 95%. Excellent retention of Zr by the vesicle membrane for up to 7 days was confirmed by PET imaging. Animal biodistribution using healthy BALB/c mice confirmed the clearance of Zr-labeled polymersomes through the spleen and liver without their accumulation in bone, unlike the free nonbound Zr radiotracer. The Zr-radiolabeled polymersomes were found to specifically target BT474 HER2-positive breast cancer cells the Tmab-TA complex on the vesicle surface. The noncovalent Tmab anchoring to the polymersome membrane can be highly advantageous for nanoparticle modification compared to currently developed covalent methods, as it allows easy and quick integration of a broad range of targeting proteins. Given the ability of these polymersomes to encapsulate and release anticancer therapeutics, they can be further expanded as precision-targeted therapeutic carriers for advancing human health through highly effective drug delivery strategies.
能够通过正电子发射断层扫描（PET）轻松成像的放射性标记药物纳米载体非常重要，因为其结果可以通过PET以高灵敏度进行定量追踪。然而，大多数PET引导的治疗诊断载体的典型放射性标记利用螯合剂配体进行修饰，这带来了各种挑战。此外，与被动肿瘤靶向不同，药物递送载体与过表达的癌细胞受体的结合亲和力对于改善肿瘤的治疗诊断递送至关重要。在此，我们通过无螯合剂放射性标记开发了尺寸为60nm的Zr标记三嵌段共聚物聚合物囊泡。该聚合物囊泡由聚（乙烯基吡咯烷酮）-聚（二甲基硅氧烷）-聚（乙烯基吡咯烷酮）（PVPON-PDMS-PVPON）三嵌段共聚物组装而成，然后通过氢键作用在聚合物囊泡表面吸附可降解的单宁酸（TA）。TA作为Zr放射性核素和靶向重组人源化单克隆抗体曲妥珠单抗（Tmab）的锚定层。与裸露的PVPON-PDMS-PVPON聚合物囊泡不同，TA和Tmab修饰的聚合物囊泡显示出超过95%的高放射化学产率。PET成像证实囊泡膜对Zr的保留率极佳，长达7天。使用健康BALB/c小鼠的动物生物分布研究证实，与游离的未结合Zr放射性示踪剂不同，Zr标记的聚合物囊泡通过脾脏和肝脏清除，不会在骨骼中积累。发现Zr放射性标记的聚合物囊泡通过囊泡表面的Tmab-TA复合物特异性靶向BT474 HER2阳性乳腺癌细胞。与目前开发的共价方法相比，Tmab非共价锚定在聚合物囊泡膜上对于纳米颗粒修饰可能具有很大优势，因为它允许轻松快速地整合多种靶向蛋白。鉴于这些聚合物囊泡能够封装和释放抗癌治疗药物，它们可以进一步扩展为精准靶向治疗载体，通过高效的药物递送策略促进人类健康。
