Self-Assembly Of Retinoid Nanoparticles For Melanoma Therapy

Abstract

Background

Amphiphilic fusion drugs are covalent conjugates of a lipophilic drug and a hydrophilic drug or their active fragments. These carrier-free self-assembly nanomaterials are helpful to co-deliver two synergic drugs to the same site regardless of pharmacokinetic properties of individual drugs. Retinoic hydroxamic acid (RHA) is a “fusion drug” of all-trans retinoic acid (ATRA) and vorinostat, a histone deacetylase (HDAC) inhibitor showing synergic effect with ATRA on cancer therapy. Although RHA was synthesized in 2005, its nanoscale self-assembly property, anticancer activity, and possible related mechanism are still unclear.

Methods

RHA nanoparticles were observed under transmission electron microscope (TEM). Both in vitro cell viability, colony formation assay, and in vivo xenograft mouse tumor model were employed here to study anticancer activity of RHA nanoparticles. The putative synergic anticancer mechanism of activating retinoic acid receptor (RAR) and inhibiting HDAC were investigated via receptor inhibitor rescue assay and in vitro enzyme activity assay, respectively.

Results

RHA could form nanoparticle formation by self-assembly and abrogates growth of several solid tumor cell lines even after RHA nanoparticles' washout. However, opposite to our initial hypothesis, pre-treating the melanoma cells with RAR antagonists showed no impact on inhibitory effect of RHA nanoparticles, which suggested that the target of the molecule on melanoma cells is not RAR and retinoid X receptor (RXR). Importantly, RHA nanoparticles inhibited the growth of xenograft tumors without obvious impact on haematological indexes and hepatorenal function of these tumor-bearing mice.

Conclusion

Our findings demonstrate the promise of RHA nanoparticles in treating malignant melanoma tumors with high efficacy and low toxicity.

Keywords:

• nano-drugs
• self-assembly
• retinoid
• cancer therapy
• melanoma

Acknowledgments

We thank DNL2001 and DNL2002 labs of Dalian Institute of Chemical Physics for providing technical supports of MS, NMR, and TEM. We also thank our present and past technicians, Xin Guo, Dan Sun, Luyao Deng, and Yi Zang, for routine technical supports and cell line maintaining.

Funding

This work is supported by the innovation program (DICP TMSR201601) of science and research from the Dalian Institute of Chemical Physics, Chinese Academy of Science, and National Natural Science Foundation of China (No.31470944).

Disclosure

Dr Han Liao reports a patent retinoic hydroxamic acids and their application in cacner therapy pending. All authors declare they have no other conflicts of interest in this work.