Fischell Department of Bioengineering , University of Maryland , College Park , Maryland 20742 , United States.
Department of Chemistry , University of British Columbia , Vancouver , British Columbia V6T 1Z1 , Canada.
Bioconjug Chem. 2019 Mar 20;30(3):525-530. doi: 10.1021/acs.bioconjchem.8b00755. Epub 2019 Feb 11.
Multidrug resistance (MDR) is a significant challenge in the treatment of many types of cancers as membrane-associated transporters actively pump drugs out of the cell, limiting therapeutic efficacy. While nanoparticle (NP)-based therapeutics have emerged as a mechanism for overcoming MDR, they often rely on the delivery of multiple anticancer drugs, nucleic acid hybrids, or MDR pump inhibitors. The effectiveness of these strategies, however, can be limited by their off-target toxicity or the need for genetic transfection. In this paper, we describe a NP-peptide-drug bioconjugate that achieves significant cell killing in MDR-positive cancer cells without the need for additional drugs. We use a quantum dot (QD) as a central scaffold to append two species of peptide, a cell-uptake peptide to facilitate endocytic internalization and a peptide-drug conjugate that is susceptible to cleavage by esterases found within the endocytic pathway. This approach relies on spatiotemporal control over drug release, where endosomes traffic drug away from membrane-resident pumps and release it closer to the nucleus. Cellular internalization studies showed high uptake of the NP-drug complex and nuclear localization of the drug after 48 h in MDR-positive cells. Additionally, cellular proliferation assays demonstrated a 40% decrease in cell viability for the NP-drug bioconjugate compared to free drug, confirming the utility of this system in overcoming MDR in cancer cells.
多药耐药性（MDR）是治疗多种癌症的重大挑战，因为膜相关转运蛋白将药物主动泵出细胞，限制了治疗效果。虽然基于纳米颗粒（NP）的治疗方法已成为克服 MDR 的一种机制，但它们通常依赖于多种抗癌药物、核酸杂交物或 MDR 泵抑制剂的递送来实现。然而，这些策略的有效性可能会受到其非靶向毒性或基因转染的需求的限制。在本文中，我们描述了一种 NP-肽-药物偶联物，它无需额外的药物即可在 MDR 阳性癌细胞中实现显著的细胞杀伤。我们使用量子点（QD）作为中央支架来附加两种肽，一种是细胞摄取肽，以促进内吞内化，另一种是肽-药物偶联物，易被内吞途径中的酯酶切割。这种方法依赖于药物释放的时空控制，其中内体将药物从膜驻留泵中运走，并将其释放到更靠近细胞核的位置。细胞内化研究表明，NP-药物复合物在 MDR 阳性细胞中 48 小时后具有高的细胞摄取和药物的核定位。此外，细胞增殖测定表明，NP-药物偶联物与游离药物相比，细胞活力降低了 40%，证实了该系统在克服癌症细胞 MDR 中的实用性。
