Poly(2-oxazoline)-Based Amphiphilic Gradient Copolymers as Nanocarriers for Losartan: Insights into Drug–Polymer Interactions

Abstract

The current study is focused on the development of highly stable drug nanocarriers by encapsulating losartan potassium (LSR) into an amphiphilic biocompatible poly(2-methyl-2-oxazoline)-grad-poly(2-phenyl-2-oxazoline) (PMeOxz72-grad-PPhOxz28) gradient copolymer (GC). Based on dynamic light scattering (DLS), the PMeOxz72-grad-PPhOxz28 (where the subscripts denote %wt composition of the components) GC formed micelles and aggregates of 13 nm and 96 nm in aqueous milieu. The presence of hydrophobic LSR molecules altered the structural characteristics of the GC, modulating the organization of the polymeric components and revealing the formation of hyper micellar nanostructures in addition to micelles. The 2D-NOESY experiments evidenced intermolecular interactions between the phenyl ring of LSR with the phenyl group of PPhOxz and eminent correlations between the butyl chain of LSR with the phenyl group of PPhOxz and methylene group of PMeOxz, respectively. Additionally, NMR studies as a function of temperature demonstrated that the presence of hydrophilic PMeOxz segments in the gradient core of PMeOxz72-grad-PPhOxz28 nanoassemblies induced an increased fluidity of the core matrix, especially upon heating, thus causing water penetration, resulting in increased proton mobility. Lastly, the ultrasound release profile of LSR signified that a great amount of the encapsulated LSR is tightly bound to the PMeOxz72-grad-PPhOxz28 nanoassemblies.

Alkyl Chain Length in Poly(2-oxazoline)-Based Amphiphilic Gradient Copolymers Regulates the Delivery of Hydrophobic Molecules: A Case of the Biodistribution and the Photodynamic Activity of the Photosensitizer Hypericin

“…It has been reported elsewhere in the literature that the nanoparticles formed by the self-assembly of amphiphilic gradient copolymers of 2-methyl-and 2-phenyl-2-oxazoline had three distinct populations that differed in size and intensityweighted size distribution of DLS plots. 19,20,61 These three populations were unimers (size < 10 nm), nanoparticles (size > 10 nm), and large aggregates (size > 100 nm). Among these, the large aggregates were the most prominent in the intensityweighted size distribution plot.…”

“…It was concluded that the formation of large aggregates may be related to the gradient structure of the copolymer chains, which allows greater exposure of the hydrophobic segments to the aqueous environment, facilitating the hydrophobic interaction between the nanoparticles. 19,20,61 Previously, we have shown that the nanoparticles formed by the self-assembly of amphiphilic gradient copolymers of 2-ethyl-and 2-(4-dodecyloxyphenyl)-2-oxazoline also exhibit two distinct populations (one with a size >10 nm and another with a size >100 nm) in the intensity-weighted size distribution plot. 21 In the present study, a closer look at the volume-weighted size distribution of the nanoparticles (Figure 3A) also shows a bimodal distribution except for the (EtOx) 88grad-(HexOPhOx) 12 nanoparticles, indicating two distinct populations.…”

“…Poly(2-methyl-2-oxazoline-grad-2-phenyl-2oxazoline) was successfully used for the encapsulation of indomethacin 19 and losartan. 20 Recently, we synthesized a new gradient copolymer of 2-ethyl-2-oxazoline and 2-(4dodecyloxyphenyl)-2-oxazoline, PEtOx-grad-DOPhOx, for the formulation of curcumin. 21 The as-prepared curcumin-loaded nanoparticles exhibited excellent colloidal stability and enhanced the in vitro bioavailability of curcumin in cancer cell lines U87 MG and HeLa.…”

“…Notably, the gradient copolymer formed smaller particles than the analogous block copolymer. Poly­(2-methyl-2-oxazoline- grad -2-phenyl-2-oxazoline) was successfully used for the encapsulation of indomethacin and losartan . Recently, we synthesized a new gradient copolymer of 2-ethyl-2-oxazoline and 2-(4-dodecyloxyphenyl)-2-oxazoline, PEtOx- grad -DOPhOx, for the formulation of curcumin .…”

Influence of Hydrophobic Side-Chain Length in Amphiphilic Gradient Copoly(2-oxazoline)s on the Therapeutics Loading, Stability, Cellular Uptake and Pharmacokinetics of Nano-Formulation with Curcumin

“…Numerous research papers have reported the promising potential of amphiphilic block copoly(2-oxazoline)-based delivery systems for the entrapment of anticancer drugs with an exceptionally high loading capacity and targeted delivery to cancer cells [28][29][30]. Recently, attempts have been made to investigate the potential of amphiphilic gradient copoly(2-oxazoline)s for the formulation of hydrophobic drugs [31][32][33][34]. Poly(2-methyl-2-oxazoline-grad-2-phenyl-2-oxazoline) (PMeOx-grad-PhOx) is the most studied gradient copoly(2-oxazoline) for drug encapsulation, containing 2-methyl-2-oxazoline (MeOx) as a hydrophilic monomer and 2-phenyl-2-oxazoline (PhOx) as a lipophilic monomer.…”