Pharmacophore hybridisation and nanoscale assembly to discover self-delivering lysosomotropic new-chemical entities for cancer therapy
| Autor: | Megan R. Showalter, Bei Jia, Jin Li, Minyong Li, Cristabelle De Souza, Yuanpei Li, Tzu-yin Lin, Kai Lin, Zhao Ma, Yuyou Duan, Shiro Urayama, Mythili Ramachandran, Dalin Zhang, Oliver Fiehn, Aaron Lindstrom, Lucas N. Solano |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
General Physics and Astronomy Drug Delivery Systems 0302 clinical medicine Neoplasms Nanotechnology lcsh:Science Cancer media_common Tumor Multidisciplinary Drug discovery Chemistry Nanomedicine Drug development 5.1 Pharmaceuticals 030220 oncology & carcinogenesis Drug delivery Aminoquinolines Development of treatments and therapeutic interventions Pharmacophore Drug Combination therapy Science Drug Compounding media_common.quotation_subject Antineoplastic Agents Bioengineering Article General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences Rare Diseases In vivo Autophagy Animals Humans Drug discovery and development Cell Proliferation General Chemistry Rats Orphan Drug 030104 developmental biology Cancer research Nanoparticles lcsh:Q Sprague-Dawley Lysosomes |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-12 (2020) Nature communications, vol 11, iss 1 Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-020-18399-4 |
| Popis: | Integration of the unique advantages of the fields of drug discovery and drug delivery is invaluable for the advancement of drug development. Here we propose a self-delivering one-component new-chemical-entity nanomedicine (ONN) strategy to improve cancer therapy through incorporation of the self-assembly principle into drug design. A lysosomotropic detergent (MSDH) and an autophagy inhibitor (Lys05) are hybridised to develop bisaminoquinoline derivatives that can intrinsically form nanoassemblies. The selected BAQ12 and BAQ13 ONNs are highly effective in inducing lysosomal disruption, lysosomal dysfunction and autophagy blockade and exhibit 30-fold higher antiproliferative activity than hydroxychloroquine used in clinical trials. These single-drug nanoparticles demonstrate excellent pharmacokinetic and toxicological profiles and dramatic antitumour efficacy in vivo. In addition, they are able to encapsulate and deliver additional drugs to tumour sites and are thus promising agents for autophagy inhibition-based combination therapy. Given their transdisciplinary advantages, these BAQ ONNs have enormous potential to improve cancer therapy. Integration of the unique advantages of the fields of drug discovery and drug delivery is invaluable for the advancement of drug development. Here, the authors generate single-drug nanoparticles by hybridising lysomotropic detergents and the bisaminoquinoline-based autophagy inhibitor, and show their therapeutic potential as autophagy-inhibition based combination therapy. |
| Databáze: | OpenAIRE |
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