Nanocarrier Composed of Magnetite Core Coated with Three Polymeric Shells Mediates LCS-1 Delivery for Synthetic Lethal Therapy of BLM-Defective Colorectal Cancer Cells.

Abstract:

:Synthetic lethality is a molecular-targeted therapy for selective killing of cancer cells. We exploited a lethal interaction between superoxide dismutase 1 inhibition and Bloom syndrome gene product (BLM) defect for the treatment of colorectal cancer (CRC) cells (HCT 116) with a customized lung cancer screen-1-loaded nanocarrier (LCS-1-NC). The drug LCS-1 has poor aqueous solubility. To overcome its limitations, a customized NC, composed of a magnetite core coated with three polymeric shells, namely, aminocellulose (AC), branched poly(amidoamine), and paraben-PEG, was developed for encapsulating LCS-1. Encapsulation efficiency and drug loading were found to be 74% and 8.2%, respectively. LCS-1-NC exhibited sustained release, with ∼85% of drug release in 24 h. Blank NC (0.5 mg/mL) exhibited cytocompatibility toward normal cells, mainly due to the AC layer. LCS-1-NC demonstrated high killing selectivity (104 times) toward BLM-deficient HCT 116 cells over BLM-proficient HCT 116 cells. Due to enhanced efficacy of the drug using NC, the sensitivity difference for BLM-deficient cells increased to 1.7 times in comparison to that with free LCS-1. LCS-1-NC induced persistent DNA damage and apoptosis, which demonstrates that LCS-1-NC effectively and preferentially killed BLM-deficient CRC cells. This is the first report on the development of a potential drug carrier to improve the therapeutic efficacy of LCS-1 for specific killing of CRC cells having BLM defects.

journal_name

Biomacromolecules

journal_title

Biomacromolecules

authors

Gupta A,Ahmad A,Singh H,Kaur S,K M N,Ansari MM,Jayamurugan G,Khan R

doi

10.1021/acs.biomac.7b01607

subject

Has Abstract

pub_date

2018-03-12 00:00:00

pages

803-815

issue

3

eissn

1525-7797

issn

1526-4602

journal_volume

19

pub_type

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