β-Lapachone Micellar Nanotherapeutics for Non–Small Cell Lung Cancer Therapy

Abstract

Lung cancer is the leading cause of cancer-related deaths with current chemotherapies lacking adequate specificity and efficacy. β-Lapachone (β-lap) is a novel anticancer drug that is bioactivated by NAD(P)H:quinone oxidoreductase 1, an enzyme found specifically overexpressed in non-small cell lung cancer (NSCLC). Herein, we report a nanotherapeutic strategy that targets NSCLC tumors in two ways: (a) pharmacodynamically through the use of a bioactivatable agent, β-lap, and (b) pharmacokinetically by using a biocompatible nanocarrier, polymeric micelles, to achieve drug stability, bioavailability, and targeted delivery. β-Lap micelles produced by a film sonication technique were small (∼30 nm), displayed core-shell architecture, and possessed favorable release kinetics. Pharmacokinetic analyses in mice bearing subcutaneous A549 lung tumors showed prolonged blood circulation (t 1/2 , ∼28 h) and increased accumulation in tumors. Antitumor efficacy analyses in mice bearing subcutaneous A549 lung tumors and orthotopic Lewis lung carcinoma models showed significant tumor growth delay and increased survival. In summary, we have established a clinically viable β-lap nanomedicine platform with enhanced safety, pharmacokinetics, and antitumor efficacy for the specific treatment of NSCLC tumors. Cancer Res; 70(10); 3896-904. ©2010 AACR.

The performance of expansile nanoparticles in a murine model of peritoneal carcinomatosis

“…As we know, nanoparticles can increase the solubility of hydrophobic drugs, provide a more consistent level of drug in the body through sustained release, protect sensitive drugs from low pH environments or enzymatic alteration, and, in some cases, provide targeting of the drug to the desired tissues [16]. Although several natural and synthetic polymers have been investigated, poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) are the most widely studied due to availability and biocompatibility.…”

Inhibition of hypoxia-induced epithelial mesenchymal transition by luteolin in non-small cell lung cancer cells

“…However, the identification of anti-metastatic agents remains unsuccessful at this point. It is widely recognized that tubular epithelial cells can differentiate into myofibroblasts via the EMT process, which plays an essential role in the development of NSCLC metastasis (20,21). A phenotypic change causes the cells to become increasingly migratory and invasive (22).…”

Leveraging an NQO1 bioactivatable drug for tumor-selective use of poly (ADP-ribose) polymerase (PARP) inhibitors

“…The MiaPaCa2 and A549 data showed significant synergy at three doses of each agent (η=0.86; SEM=0.33) (Chou and Talalay, 1984;Lee et al, 2007). Rucaparib + β-lap showed no signs of methemoglobinemia (i.e., labored breathing, lethargy in 45 min), noted with higher doses of β-lap (~30 mg/kg, iv) alone (Blanco et al, 2010;Huang et al, 2012). No significant weight loss or long-term normal tissue toxicities (liver, lung, pancreas, kidney, spleen, colon, etc.)…”

“…Bioluminescence (BLI)-based tumor volumes, long-term survival and target validation assays were performed with log-rank tests for survival (Blanco et al, 2010;Ma et al, 2015). Pharmacokinetics (PK) of Rucaparib or β-lap levels in blood and tumor were assessed by LC-MS/MS analyses following extraction of plasma or tumor homogenates with acetonitrile (Blanco et al, 2010;Ma et al, 2015). An unpaired t-test (GraphPad QuickCalcs, San Diego, CA) was used significant differences in β-lap concentrations after different treatments.…”