Nitric oxide-releasing graft polymer micelles with distinct pendant amphiphiles

Abstract

Polymeric micelle is a versatile nanoscale platform for sustained release of short-lived nitric oxide (NO). The aim of this work was to better understand the correlation between polymer architecture and NO release kinetics. Stable nitrate was selected as the NO donor and co-conjugated to a multivalent polymer backbone together with amphiphilic methoxy poly(ethylene glycol) and poly(lactic acid) (mPEG-PLA), or D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). Both graft polymers could self-assemble into micellar nanocarriers with a size less than 100 nm. The weight-based NO loading was 4.92% (w/w) and 6.05% (w/w) for mPEG-PLA-and TPGS-modified micelles, respectively. The former is less stable than the later with a corresponding critical micelle concentration of 23.9 ± 2.0 nM and 9.8 ± 0.5 nM. Using the standard Griess assay, it was shown that both micelles could achieve sustained NO release in vitro. However, the TPGS-modified nanocarrier exhibited a delayed onset, but faster steady-state release of NO in comparison to its counterpart. This was primarily due to folded PEG conformation and its high packing surface density. These results illustrate the potential utility of polymer architecture engineering to precisely tune the NO release behavior for ultimately optimum therapeutic outcome.

Delivery of Nitric Oxide in the Cardiovascular System: Implications for Clinical Diagnosis and Therapy

“…Incorporating polymers into a NO release platform allows delivering NO in a more continuous manner, including through micelles, dendrimers, star-shaped polymers, and polymeric nanoparticles [90]. Micelles use amphiphilic polymers to synthesize concentration-dependent structures through hydrophilic or hydrophobic interactions but have a low encapsulation efficiency [36,[90][91][92]. Dendrimers are three-dimensional hyperbranched globular nanopolymeric architectures with the advantages of a narrow polydispersity index, controllable structure, and the availability of multiple functional groups at the periphery [93][94][95].…”

Progress and Prospects of Regulatory Functions Mediated by Nitric Oxide on Immunity and Immunotherapy

“…[ 119] Sodium nitroprusside 2 min [ 120] trans-[Ru(NH 3 ) 4 (py)(NO)] 3+ 0.06 s −1 [ 121] Nitrosothiol Nitrosothiol releases NO through homolytic and heterolytic cleavage of S─N bond under the catalysis of temperature, light, and metal ions, or exerts biological activity through S-nitrosylation/trans-S-nitrosylation. [98] S-nitrosoglutathione 0.018 h −1 [ 122] N-acetylpenicill-amine 4 h [ 123] tert-butyl S-nitrosothiol N/A S-nitrosocysteine 1.42 h −1 [ 122] NO-delivery systems NO-delivery systems are universally modified by active groups of NO donors or encapsulated NO donors NOPP/NPs 0.0374 × 10 −6 m mg −1 [ 101] PROLI/NO DPPC Lipo 0.16 ± 0.05 h [ 102] DEA 1.37 h −1 [ 104] PHEMA-(DNO) 107 -(TPGS) 46 1.72 h −1 -gal-NONOate 5 min [ 110] -gal-NONOate Lipo 2.5 h a) If not specified, the plasma half-life of the clinical drug is recorded (healthy volunteers, intravenous administration), and the half-life or rate of NO release of preclinic drug is recorded.…”

“…[98] S-nitrosoglutathione 0.018 h −1 [ 122] N-acetylpenicill-amine 4 h [ 123] tert-butyl S-nitrosothiol N/A S-nitrosocysteine 1.42 h −1 [ 122] NO-delivery systems NO-delivery systems are universally modified by active groups of NO donors or encapsulated NO donors NOPP/NPs 0.0374 × 10 −6 m mg −1 [ 101] PROLI/NO DPPC Lipo 0.16 ± 0.05 h [ 102] DEA/NO DPPC Lipo 0. Pluronic F127-BPEI-NONOates (FBN) 5.9 min [ 103] FBN/PEG 23.4 min PHEMA-(DNO) 121 -(mPEG-PLA) 32 1.37 h −1 [ 104] PHEMA-(DNO) 107 -(TPGS) 46 1.72 h −1 𝛽-gal-NONOate 5 min [ 110] 𝛽-gal-NONOate Lipo 2.5 h a) If not specified, the plasma half-life of the clinical drug is recorded (healthy volunteers, intravenous administration), and the half-life or rate of NO release of preclinic drug is recorded.…”

“…The duration of the slow release of NO from micelle‐based TPGS side chain was 32 h, while the duration of the slow release of NO from mPEG–PLA side‐chain micelles was 13 h, which indicated that choosing different polymer side chains could adjust the NO release kinetics. [ 104 ] Latanoprost–butanediol mononitrate eye drops VYZULTA, which has been on the market, can be quickly hydrolyzed in the eyes to obtain latanoprost acid and butanediol mononitrate. The former acts on the uveoscleral pathway and interacts with prostaglandin F2α receptor binding to upregulate the release of matrix metalloproteinases, enhance the digestion of extracellular matrix, and promote the drainage of aqueous humor from the uveoscleral pathway.…”

The Delivery of Nitric Oxide in the Cardiovascular System: Implication for Clinical Diagnosis and Therapy

“…Incorporating polymers into NO releasing platform allows transporting NO in a more continuous manner, including micelles, dendrimers, star-shaped polymers, and polymeric nanoparticles [128]. Micelles use amphiphilic polymers to synthesize concentration-dependent structures through hydrophilic or hydrophobic interactions, but have low encapsulation efficiency [128][129][130][131]. Dendrimers are three-dimensional hyperbranched globular nanopolymeric architectures with advantages of narrow polydispersity index, controllable structure and availability of multiple functional groups at the periphery [132][133][134].…”