The Daniel K. Inouye College of Pharmacy Scripts: Targeted Nanocarrier Based Systems for the Treatment of Lung Cancer

Abstract

In Hawai'i, lung cancer is among the top cancers diagnosed and a leading cause of death. Despite current understanding and modern surgery, radiology, and chemotherapy techniques, the survival of those suffering from lung cancer remains low. Current anticancer drugs have poor tumor tissue selectivity and toxicity issues that contribute to their overall low efficacy, detrimental effects to normal tissues, and drug resistance. A potential way of mitigating cancer is through RNA interference (RNAi) by the delivery of small interfering RNA (siRNA) to target select proteins or genes involved in cancer progression, known as oncoproteins or oncogenes, respectively. However, the clinical utility of delivering unformulated siRNA has been hindered due to poor cell penetration, nonspecific effects, rapid degradation, and short half-life. As an alternate for conventional chemotherapy, nanoparticles (AKA nanocarriers) may be designed to localize within the tumor environment and increase targeted cell internalization, thus reducing systemic adverse effects and increasing efficacy. Nanoparticles play important roles in drug delivery and have been widely studied for cancer therapy and diagnostics, termed collectively as theranostics. Nanoparticles composed of natural and artificial polymers, proteins, lipids, metals, and carbon-based materials have been developed for the delivery of siRNA. Cancer targeting has been improved by nanoparticle surface modification or conjugation with biomolecules that are attracted to or stimulate therapeutic agent release within cancer tissues or cells. In this mini-review article, we present recent progress in nanocarrier-mediated siRNA delivery systems that include lipid, polymer, metallic and carbon-based nanoparticles for lung cancer therapy.

Figure 1

A timeline showing the history of major cancer nanomedicine breakthroughs. Figure adapted with permission from Nature Publishing Group: Nature Reviews Cancer, 2017.

Figure 2

Schematic illustration and representative TEM images of PolyMet nanoparticles. Anionic HA + siRNA mixture was condensed by cationic PolyMet into negatively charged PolyMet (HA+ siRNA) complex (a, c). DOTAP/cholesterol cationic liposomes were added to the complex to form lipid coating, then DSPE-PEG and DSPE-PEG-anisamide were used to prepare a liposome using the post-insertion method to form LPH-PolyMet nanoparticles (b,d). By Zhao, et al, 2016. Used under Creative Commons Attribution 4.0.

Figure 3

Synthesis and physicochemical characterization of siRNA-FNP. a Scheme showing HuR-FNP preparation. b TEM image of NP, HuR-NP, and HuR-FNP. Scale bar denotes 100 nm. c Agarose gel electrophoretogram showing siRNA protection by FNP at different time (0, 0.5, and 1 hr) points of incubation compared to naked siRNA exposed to serum for 1 hr. Free siRNA not exposed to serum was used as an internal marker. d siRNA release profile over time from siRNA-FNP in PBS (pH 7.4) measured by Quanti-iT Picogreen Assay (top figure); and from fluorescently labeled siRNA (siGLO)-FNP in acetate buffer (pH 5.5) and in 50% FBS containing PBS (pH 7.4) (bottom figure). By Muralidharanet, al, 2016. Used under Creative Commons Attribution 4.0.

Figure 4

a Schematic representation of chitosan-deoxycholic acid coated perfluoropentane nanodroplets (CNDs). b Hydrodynamic diameters of CNDs before (solid line) and after (dotted line) exposure to ultrasound for 45 s in 10% glycerol in water. c Zeta potential of CNDs before and after ultrasound exposure. d TEM images of CND before (left) and after (right) ultrasound exposure for 45 s. By Lee, et al, 2017. Used under Creative Commons Attribution 4.0.