Abstract
Drugs are administered orally in the clinical treatment of hypertension. Antihypertensive peptides have excellent angiotensin converting enzyme inhibitors activity in vitro. However, the poor oral bioavailability and therapeutic effect of antihypertensive peptides were mainly caused by rapid degradation in gastrointestinal and the short circulation time in blood, which remain to be further optimized. Therefore, the novel oral peptide delivery system is urged to improve the oral absorption and efficacy of peptide drugs. In this work, Tyr-Gly-Leu-Phe (YF4)-loaded lipid nanoparticles (YF4-LNPs) combined the advantages of polymer nanoparticles and liposomes were developed, which could greatly enhance the oral bioavailability and ameliorate the sustained release of peptide drug. YF4 loaded nanoparticles (YF4-NPs) were firstly prepared by a double-emulsion internal phase/organic phase/external phase (W1/O/W2) solvent evaporation method. YF4-NPs were further coated by membrane hydration-ultrasonic dispersion method to obtain the YF4-LNPs. The optimal YF4-LNPs showed a small particle size of 227.3 ± 3.8 nm, zeta potential of -7.27 ± 0.85 mV and high entrapment efficiency of 90.28 ± 1.23%. Transmission electronic microscopy analysis showed that the core-shell lipid nanoparticles were spherical shapes with an apparent lipid bilayer on the surface. Differential scanning calorimetry further proved that YF4 was successfully entrapped into YF4-LNPs. The optimal preparation of YF4-LNPs exhibited sustained release of YF4 in vitro and a 5 days long-term antihypertensive effect in vivo. In summary, the lipid nanoparticles for oral antihypertensive peptide delivery were successfully constructed, which might have a promising future for hypertension treatment.
Highlights
Nanotechnology has been widely used to improve the oral absorption and therapeutic efficacy of small molecule peptide drugs, which have shown tremendous potentials but great challenges (Olbrich et al, 2001; Tan et al, 2009; Li et al, 2013; Yang et al, 2013; Thi et al, 2015; Wang et al, 2018)
Several factors that could affect the features of YF4-LNPs were systematically optimized to produce the desirable YF4-LNPs, including the Poly-(lactic-co-glycolic) acid (PLGA) concentration, the volume of acetone in the organic phase, the volume of the inner aqueous medium, the pH of the aqueous medium, the external water phase, the PVA concentration, the PVA volume, the ultrasonic time, PLGA to lipid material ratio, and the ultrasound power
The influence of PLGA concentration on the EE and particle size was investigated in Figure 1A.The EE and the particle size were positively correlated with the PLGA amount within the range of 10–50 mg
Summary
Nanotechnology has been widely used to improve the oral absorption and therapeutic efficacy of small molecule peptide drugs, which have shown tremendous potentials but great challenges (Olbrich et al, 2001; Tan et al, 2009; Li et al, 2013; Yang et al, 2013; Thi et al, 2015; Wang et al, 2018). Liposomes have been applied for drug delivery due to the superior biocompatibility, drug absorption and nontoxicity (Wang and Liu, 2013). Both of them have some unsatisfied disadvantages in peptide delivery, such as leakage and safety issues, which seriously limited the delivery efficiency. The dual advantages of the particles and vesicle make it an excellent oral drug carrier with high biocompatibility and sustained release (Xie et al, 2018). In this system, drugs can be efficiently encapsulated in the nanoparticles core and/or the lipid bilayers, resulted in increased drug load capability. It is still challenging to achieve high encapsulation efficiency (EE) and decent particle size when incorporating hydrophilic drugs into LNPs
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