Dual drug-loaded biofunctionalized amphiphilic chitosan nanoparticles: Enhanced synergy between cisplatin and demethoxycurcumin against multidrug-resistant stem-like lung cancer cells

Abstract

Lung cancer kills more humans than any other cancer and multidrug resistance (MDR) in cancer stem-like cells (CSC) is emerging as a reason for failed treatments. One concept that addresses this root cause of treatment failure is the utilization of nanoparticles to simultaneously deliver dual drugs to cancer cells with synergistic performance, easy to envision - hard to achieve. (1) It is challenging to simultaneously load drugs of highly different physicochemical properties into one nanoparticle, (2) release kinetics may differ between drugs and (3) general requirements for biomedical nanoparticles apply. Here self-assembled nanoparticles of amphiphilic carboxymethyl-hexanoyl chitosan (CHC) were shown to present nano-microenvironments enabling simultaneous loading of hydrophilic and hydrophobic drugs. This was expanded into a dual-drug nano-delivery system to treat lung CSC. CHC nanoparticles were loaded/chemically modified with the anticancer drug cisplatin and the MDR-suppressing Chinese herbal extract demethoxycurcumin, followed by biofunctionalization with CD133 antibody for enhanced uptake by lung CSC, all in a feasible one-pot preparation. The nanoparticles were characterized with regard to chemistry, size, zeta potential and drug loading/release. Biofunctionalized and non-functionalized nanoparticles were investigated for uptake by lung CSC. Subsequently the cytotoxicity of single and dual drugs, free in solution or in nanoparticles, was evaluated against lung CSC at different doses. From the dose response at different concentrations the degree of synergy was determined through Chou-Talalay's Plot. The biofunctionalized nanoparticles promoted synergistic effects between the drugs and were highly effective against MDR lung CSC. The efficacy and feasible one-pot preparation suggests preclinical studies using relevant disease models to be justified.

Drug Targeting Strategies Based on Charge Dependent Uptake of Nanoparticles into Cancer Cells

“…These polymeric NPs (with the average particle size of 100 nm and ZP of -3 mV) consisted of amphiphilic carboxymethylhexanoyl chitosan (CHC), cisplatin, and the MDRsuppressing Chinese herbal extract: demethoxycurcumin. They were bio-functionalized by CD133 antibody for enhanced uptake by A549-ON lung cancer stem-like cells (CSC) (166).…”

Development of novel PLGA nanoparticles with co‐encapsulation of docetaxel and abiraterone acetate for a highly efficient delivery into tumor cells

“…Therefore, co‐encapsulation of AbrA and Dtx increases the cytotoxic activity of these substances as compared to their use as a combination of free drugs, which has shown antagonism of their use at given ratio. Likely, encapsulation and subsequent accumulation in cells alter the stability of the drugs and their transport kinetics, and also lead to simultaneous intracellular release of the two drugs which ultimately determines the observed result, expressed in the best effect .…”

Current perspectives on the crosstalk between lung cancer stem cells and cancer-associated fibroblasts

“…Hu5F9-G4 and CC-90002) in treating patients with hematological malignancies and advanced solid tumors (ClinicalTrials.gov Identifier: NCT02678338 and NCT02216409). Likewise, CD133 targeted antibodies alone, conjugated or biofunctionalized on the surface of nanoparticles are also being tested against CSCs, but currently such therapies are still at the pre-clinical level (Huang et al, 2016;Prasad et al, 2015). Taken together, while some advances have been made , we are still far from capitalizing on CSC markers as an efficient means to identify, isolate and/or target these cells.…”