CDC20siRNA and paclitaxel co-loaded nanometric liposomes of a nipecotic acid-derived cationic amphiphile inhibit xenografted neuroblastoma

Abstract

Despite significant recent progress in the area of translational genomics of neuroblastoma, the overall survival rates for children with high-risk NB continue to be not more than 5 years due to tumor relapse and/or drug-resistant tumors. Herein we report on the development of a neuroblastoma targeting nanometric (130-150 nm) circulation stable liposomal system prepared from a novel nipecotic acid-derived cationic amphiphile (NACA). The size ranges of liposomes (130-150 nm) were confirmed by both dynamic light scattering and transmission electron microscopy. The findings in the gel electrophoresis assay revealed that siRNAs encapsulated within the liposomes of NACA (with 90% entrapment efficiency) are protected from attack by RNase. Cellular uptake experiments using FAM-siRNA loaded liposomes of NACA showed the liposomal entry in human neuroblastoma cells (IMR-32) to be mediated via the GABA receptor. CDC20siRNA-loaded liposomes of NACA caused significantly higher CDC20 gene silencing efficiency in IMR-32 cells compared to CDC20 gene knockdown efficiency mediated by CDC20siRNA-loaded control non-targeting liposomes (NTL). The findings in the annexin-V binding based flow cytometric apoptosis assay and MTT-based cellular cytotoxicity assay support the notion that pronounced (80%) neuroblastoma cell death upon treatment with CDC20siRNA & PTX co-loaded liposomes of NACA presumably originates from enhanced apoptosis of cells. Importantly, intravenously administered CDC20siRNA & PTX co-loaded liposomes of NACA significantly inhibited growth of xenografted human neuroblastoma in athymic nude mice. The presently disclosed strategy of co-delivering potent anticancer siRNA and small molecule chemotherapeutics using liposomes of NACA opens a new door for combating the dreaded disease of neuroblastoma.

<p>Targeting cell cycle protein in gastric cancer with CDC20siRNA and anticancer drugs (doxorubicin and quercetin) co-loaded cationic PEGylated nanoniosomes</p>

“…These results are in agreement with the findings of our studies reported here 18. Bhunia and colleagues, exhibited the synergistic effect of CDC20siRNA and paclitaxel, employing nanometric liposomes, which inhibited xenografted neuroblastoma 25. The synergistic effects of QC and DOX on the gene expression of CDC20 have not been fully elucidated on the gastric cancer cells.…”

Carrier-free, self-assembled pure drug nanorods composed of 10-hydroxycamptothecin and chlorin e6 for combinatorial chemo-photodynamic antitumor therapy in vivo

“…3–7 Recent years, nanomedicine has emerged as an innovative and promising strategy for more effective and safer cancer treatment. 8–11 Tremendous attention has been paid to develop various kinds of nanoscale drug delivery systems (nDDS), such as liposomes, 12–15 dendrimers, 16–18 micelles, 19–23 inorganic nanomaterials, 24–30 and so on. Two main approaches have been employed to prepare nanoformulations of anticancer drugs, including directly encapsulating drugs with nanocarriers and conjugating drugs to macromolecular nanovectors.…”

Neuroblastoma‐targeted nanoparticles and novel nanotechnology‐based treatment methods

“…The stable circulation of this liposomal system, which is delivered by intravenous administration enhances the therapeutic efficacy with experiments showing a higher efficacy of this strategy in tumor destruction in comparison with CDC20siRNA‐loaded control nontargeted liposomes. These findings indicated that co‐delivery of siRNA and chemotherapeutic drugs by NACA nano‐liposomes would be a good therapeutic option worthy of further consideration to improve NB treatment (Figure 3; Bhunia et al, 2017). Another example of encapsulating siRNAs has been shown in another study that aimed to encapsulate MYCN siRNA in a liposome coated with folate molecules.…”

“…However, the sensitivity of siRNA to RNase is a big problem that could be solved by encapsulating the siRNA in nanometric liposomes. As a result, scientists decided to design liposomes which protect siRNAs from destruction (Bhunia, Radha, & Chaudhuri, 2017; Zhu et al, 2013). Cell division cycle homolog 20 (CDC20), a protein with an important role in mitosis regulation in the cell cycle, is overexpressed in many types of cancers.…”