Aptamer-Peptide Conjugates as Targeted Chemosensitizers for Breast Cancer Treatment.

High levels of heat shock protein 70 (HSP70) in tumors are commonly associated with poor prognosis, enhanced doxorubicin (DOX)-induced cardiotoxicity, and even drug resistance in DOX-related cancer chemotherapy. Several peptides possess remarkable protein inhibition and chemosensitization effects, which are attributed to their specific targeting ability against HSP70. However, the inherent poor cell penetration capacity considerably restricts the biomedical applications of these peptides. We herein describe the design and development of anti-MUC1 aptamer-peptide conjugates (ApPCs) as targeted chemosensitizers to overcome the above-mentioned issues. Moreover, DOX could be loaded on the ApPC to deliver the DOX-enclosed agent ApPC-DOX, which simultaneously acts as a targeted chemosensitizer and anticancer agent for combating drug resistance in breast cancer therapy. This innovative, engineered biocompatible conjugate not only enhances the sensitivity of DOX-resistant cells but also alleviates cardiotoxicity of DOX in vivo, highlighting the success of this targeted chemosensitizer strategy.

Aptamer Enables Consistent Maytansine Delivery through Maintaining Receptor Homeostasis for HER2 Targeted Cancer Therapy.

Although the extensive clinical use of the ADC trastuzumab-DM1(T-DM1) for human epidermal growth factor receptor 2 (HER2) targeted cancer therapy, many patients who initially respond to T-DM1 treatment eventually met the insufficient efficacy issue, which is partly attributed to the decreased amount of surface HER2 caused by HER2 degradation in target cells. In our study, we have engineered a HER2 targeted DNA aptamer-DM1 conjugate (HApDC) that can maintain the homeostasis of surface HER2 on the target cancer cell. These conclusions are supported by determining the efficient internalization of HApDC into HER2 overexpressed BT474 and SKBR3 cancer cell lines and by identifying the membranal HER2 level on HApDC-treated BT474 cells. Consistent with the impressive in vitro properties of our newly developed anticancer agent, DM1 could precisely be delivered to the tumor tissue in BT474 xenografted mouse models, because of the specific recognition of aptamer. Noteworthy, HApDC exhibited excellent in vivo tumor inhibition function with much lower healthy organ toxicity, compared with the free drug, which might be explained by the persistently targeted DM1 delivery, which is attributed to the remaining HER2 levels on cells.

Anticancer-Active N-Heteroaryl Amines Syntheses: Nucleophilic Amination of N-Heteroaryl Alkyl Ethers with Amines.

A mild amination protocol of N-heteroaryl alkyl ethers with various amines is described. This transformation is achieved by utilizing simple and readily available base as promoter via C-O bond cleavage, offering a new amination strategy to access several anticancer-active compounds. This work is highlighted by the excellent functional group compatibility, scalability, wide substrate scope, and easy derivatization of a variety of drugs.