Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy

Abstract

Paclitaxel is widely used in cancer treatments, but poor water-solubility and toxicity raise serious concerns. Here we report an RNA four-way junction nanoparticle with ultra-thermodynamic stability to solubilize and load paclitaxel for targeted cancer therapy. Each RNA nanoparticle covalently loads twenty-four paclitaxel molecules as a prodrug. The RNA-paclitaxel complex is structurally rigid and stable, demonstrated by the sub-nanometer resolution imaging of cryo-EM. Using RNA nanoparticles as carriers increases the watersolubility of paclitaxel by 32,000-fold. Intravenous injections of RNA-paclitaxel nanoparticles with specific cancer-targeting ligand dramatically inhibit breast cancer growth, with nearly undetectable toxicity and immune responses in mice. No fatalities are observed at a paclitaxel dose equal to the reported LD 50. The use of ultra-thermostable RNA nanoparticles to deliver chemical prodrugs addresses issues with RNA unfolding and nanoparticle dissociation after high-density drug loading. This finding provides a stable nano-platform for chemo-drug delivery as well as an efficient method to solubilize hydrophobic drugs.

Cryo-electron Microscopy and Exploratory Antisense Targeting of the 28-kDa Frameshift Stimulation Element from the SARS-CoV-2 RNA Genome

“…Cryo-EM structure determination of RNA-only systems or macromolecules with molecular weights under 50 kDa has been accomplished only recently 7,[35][36][37][38] , and it was unclear whether cryo-EM might be applicable to an RNA as small as the SARS-CoV-2 FSE (28 kDa, 88 nucleotides; Fig. 1a).…”

Recent Progress of Nanocarrier-Based Therapy for Solid Malignancies

“…Drugs employed in the treatment of cancer can be loaded either by entrapment within, adsorption on, or by covalently binding to the nanoparticle [ 4 ]. As shown in Figure 3 , drugs can be attached to the outer shell or the corona of NPs by covalent bonding or physical adsorption as for example by electrostatic interactions between the nanoparticle and drug, which usually exhibit low stability and become pH liable [ 90 , 91 ]. The non-covalent binding is simple, versatile in application, and the structure and biological activity of the drugs is exposed to minimal change.…”

“…Another study reported an RNA four-way junction NPs with ultra-thermodynamic stability covalently loaded with high-density PTX (RNA-PTX) for targeted cancer therapy. Results showed that RNA-PTX dramatically strongly accumulated in tumors and inhibited tumor growth with negligible toxicity in vivo [ 91 ]. Zafar and its associates developed pegylated LNCs for co-encapsulation of DTX and thymoquinone (THQ).…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–7

“…Consequently, the development of novel cancer-targeted drug delivery systems represents one of the hottest areas of modern cancer research. Recently, Guo et al [26] constructed a smart RNA-based multifunctional nanovector for targeted delivery of paclitaxel, whose use in the clinic is limited by scarce bioavailability and severe toxicity, to triple-negative breast cancer, by using aptamers for guaranteeing tumor targeting. Specifically, a "X"-shaped RNA four-way junction nanostructure with ultra-thermodynamic stability was assembled with the extraordinary loading capability of twenty-four paclitaxel molecules as the prodrug.…”