β-Lapachone and Paclitaxel Combination Micelles with Improved Drug Encapsulation and Therapeutic Synergy as Novel Nanotherapeutics for NQO1-Targeted Cancer Therapy

Abstract

β-Lapachone (LPC) is a novel cytotoxic agent that is bioactivated by NADP(H): quinone oxidoreductase 1 (NQO1), an enzyme elevated in a variety of tumors, such as non-small cell lung cancer (NSCLC), pancreatic cancer, liver cancer, and breast cancer. Despite its unique mechanism of action, its clinical evaluation has been largely hindered by low water solubility, short blood half-life, and narrow therapeutic window. Although encapsulation into poly(ethylene glycol)-b-poly(D,L-lactic acid) (PEG-PLA) micelles could modestly improve its solubility and prolong its half-life, the extremely fast intrinsic crystallization tendency of LPC prevents drug loading higher than ∼2 wt %. The physical stability of the LPC-loaded micelles is also far from satisfactory for further development. In this study, we demonstrate that paclitaxel (PTX), a front-line drug for many cancers, can provide two functions when coencapsulated together with LPC in the PEG-PLA micelles; first, as a strong crystallization inhibitor for LPC, thus to significantly increase the LPC encapsulation efficiency in the micelle from 11.7 ± 2.4% to 100.7 ± 2.2%. The total drug loading efficiency of both PTX and LPC in the combination polymeric micelle reached 100.3 ± 3.0%, and the drug loading density reached 33.2 ± 1.0%. Second, the combination of LPC/PTX demonstrates strong synergistic cytotoxicity effect against the NQO1 overexpressing cancer cells, including A549 NSCLC cells, and several pancreatic cancer cells (combination index <1). In vitro drug release study showed that LPC was released faster than PTX either in phosphate-buffered saline (PH = 7.4) or in 1 M sodium salicylate, which agrees with the desired dosing sequence of the two drugs to exert synergistic pharmacologic effect at different cell checkpoints. The PEG-PLA micelles coloaded with LPC and PTX offer a novel nanotherapeutic, with high drug loading, sufficient physical stability, and biological synergy to increase drug delivery efficiency and optimize the therapeutic window for NOQ1-targeted therapy of cancer.

Theranostic nanomaterials applied to the cancer diagnostic and therapy and nanotoxicity studies

“…In agreement with data in the literature, (124,128,130) the specific toxicity of -Lap for cancer cells was found (Figure 3.20C). -Lap induced cell death of A549 and HTC cells at a concentration of 4 and 8 µM, while HepaRG showed to be more resistant.…”

Improving Drug Delivery of Micellar Paclitaxel against Non‐Small Cell Lung Cancer by Coloading Itraconazole as a Micelle Stabilizer and a Tumor Vascular Manipulator

“…However, IM was a milky suspension with visible large micelle agglomerates (size > 200 nm) at the same 4 mg mL −1 ITA concentration as PIM (Figure S2, Supporting Information) . According to our previously study, we believe the hetero‐intermolecular interactions (e.g., π–π stacking, H‐bonding) between PTX and ITA are the critical factors contributing to the formation of a miscible system, inhibit crystallization of both ITA and PTX, and enhance the colloidal stability of the micelles …”

“…PTX/ITA Micelles Fabrication and Characterization : Coloaded PEG‐PLA micelles were prepared as previously described by a film hydration method . Briefly, appropriate amounts of PEG‐PLA (300 mg), ITA (40 mg), and PTX (40 mg) were all dissolved in acetonitrile and methanol (1:1 v/v).…”

PhytoNanotechnology: Enhancing Delivery of Plant Based Anti-cancer Drugs

“…These micelles showcased enhanced antiproliferative effect vs. the individual drug micelles (IC 50 = 0.16 mM for the co-encapsulated micelles, IC 50 = 4.5 mM for β-lapachone micelles and 0.32 mM for PTX micelles). A very useful synergistic effect was observed for the co-encapsulated two agents against lung cancer (Zhang et al, 2015). …”