Ultrasound-Triggered Phase-Transition Cationic Nanodroplets for Enhanced Gene Delivery

Abstract

Ultrasound as an external stimulus for enhanced gene transfection represents a safe, noninvasive, cost-effective delivery strategy for gene therapy. Herein, we have developed an ultrasound-triggered phase-transition cationic nanodroplet based on a novel perfluorinated amphiphilic poly(amino acid), which could simultaneously load perfluoropentane (PFP) and nucleic acids. The heptadecafluoroundecylamine (C11F17-NH2) was chosen to initiate β-benzyl-L-aspartate N-carboxyanhydride (BLA-NCA) ring-opening polymerization to prepare C11F17-poly(β-benzyl-L-aspartate) (C11F17-PBLA). Subsequently, C11F17-poly{N-[N'-(2-aminoethyl)]aspartamide} [C11F17-PAsp(DET)] was synthesized by aminolysis reaction of C11F17-PBLA with diethylenetriamine (DET). PFP/pDNA-loaded nanodroplets PFP-TNDs [PFP/C11F17-PAsp(DET)/LucDNA/γ-PGA or poly(glutamic acid)-g-MeO-poly(ethylene glycol) (PGA-g-mPEG) ternary nanodroplets] were primarily formulated by an oil/water emulsification method, followed by surface modification with PGA-g-mPEG. The average diameter of PFP-TNDs ranged from 300 to 400 nm, and transmission electron microscopy images showed that the nanodroplets were nearly spherical in shape. The ζ potential of the nanodroplets dramatically decreased from +54.3 to +15.3 mV after modification with PGA-g-mPEG, resulting in a significant increase of the stability of the nanodroplets in the serum-containing condition. With ultrasound irradiation, the gene transfection efficiency was enhanced 14-fold on HepG2 cells, and ultrasound-triggered phase-transition cationic nanodroplets also displayed a good ultrasound contrast effect. These results suggest that the PFP/DNA-loaded phase-transition cationic nanodroplets can be utilized as efficient theranostic agents for targeting gene delivery.

Cardiomyocyte-targeted and 17β-estradiol-loaded acoustic nanoprobes as a theranostic platform for cardiac hypertrophy

“…Almost all particles gradually expanded, while a large number of bubbles were generated when the temperature was further elevated to 60 °C, indicating that external temperature is a critical factor in the phase transition process of PCM-E2/PFPs. It is worth mentioned that during the process of microbubble formation, adjacent bubbles tended to coalesce with each other and form larger ones, similar to that found in previous research [ 35 ]. The strong hydrophobic interaction among PFP gases in the core of the generated microbubbles can be a good explanation for this phenomenon, which promotes adherence among bubbles.…”

<div>Low-intensity focused ultrasound (LIFU)-induced acoustic droplet vaporization in phase-transition perfluoropentane nanodroplets modified by folate for ultrasound molecular imaging</div>

“…After being encapsulated into a phospholipid shell to formulate a nano-sized droplet, the BP of FA-NDs can be elevated substantially due to the high Laplace pressure. 26 The results of in vitro thermal evaporation which could further increase their circulation time and local accumulation in tumor tissue. The common US molecular probes were produced by attaching monoclonal antibodies to the MB shell surface, whereas the large protein molecules with large diameters restrict them to freely leave the vasculature and act as real cell targeting agent.…”

Trigger-Responsive Gene Transporters for Anticancer Therapy

“…Another disadvantage of using gas phase perfluorocarbon (PFC)-containing microbubble is that they have poor resistance toward any distortions, thus leading to a short circulation time in vivo. Gao et al loaded liquid PFC into plasmid DNA-cationic nanodroplets containing the polymers C 11 F 17 -poly N -[ N ′-(2-aminoethyl)] aspartamide [C 11 F 17 -PAsp (DET)] to obtain enhanced stabilization, biocompatibility, transgene expression, and US contrast effect [153]. …”