The possibility to conjugate tumor-targeted cytotoxic nanoparticles and conventional antitumoral drugs in single pharmacological entities would open a wide spectrum of opportunities in nanomedical oncology. This principle has been explored here by using CXCR4-targeted self-assembling protein nanoparticles based on two potent microbial toxins, the exotoxin A from Pseudomonas aeruginosa and the diphtheria toxin from Corynebacterium diphtheriae, to which oligo-floxuridine and monomethyl auristatin E respectively have been chemically coupled. The resulting multifunctional hybrid nanoconjugates, with a hydrodynamic size of around 50 nm, are stable and internalize target cells with a biological impact. Although the chemical conjugation minimizes the cytotoxic activity of the protein partner in the complexes, the concept of drug combination proposed here is fully feasible and highly promising when considering multiple drug treatments aimed to higher effectiveness or when facing the therapy of cancers with acquired resistance to classical drugs.

在单一药理实体中结合靶向肿瘤的细胞毒性纳米颗粒和常规抗肿瘤药物的可能性将为纳米医学肿瘤学带来广泛的机会。通过使用靶向CXCR4的自组装蛋白纳米颗粒，基于两种有效的微生物毒素，即铜绿假单胞菌的外毒素A和白喉棒状杆菌的白喉毒素，探索了这一原理。分别与低聚氟尿苷和单甲基澳瑞他汀E化学偶联。所得的多功能杂化纳米共轭物具有约50 nm的流体动力学大小，是稳定的，并在生物学上影响靶细胞。尽管化学结合使复合物中蛋白质伴侣的细胞毒性活性最小化，但在考虑多种旨在提高疗效的药物治疗或面临对经典获得性耐药的癌症治疗时，此处提出的药物组合概念是完全可行的，并且很有希望毒品。