Rapamycin-Loaded Polymeric Nanoparticles as an Advanced Formulation for Macrophage Targeting in Atherosclerosis

Abstract

Recently, rapamycin (Rapa) represents a potential drug treatment to induce regression of atherosclerotic plaques; however, its use requires site-specific accumulation in the vessels involved in the formation of the plaques to avoid the systemic effects resulting from its indiscriminate biodistribution. In this work, a stable pharmaceutical formulation for Rapa was realized as a dried powder to be dispersed extemporaneously before administration. The latter was constituted by mannitol (Man) as an excipient and a Rapa-loaded polymeric nanoparticle carrier. These nanoparticles were obtained by nanoprecipitation and using as a starting polymeric material a polycaprolactone (PCL)/α,β-poly(N-2-hydroxyethyl)-dl-aspartamide (PHEA) graft copolymer. To obtain nanoparticles targeted to macrophages, an oxidized phospholipid with a high affinity for the CD36 receptor of macrophages, the 1-(palmitoyl)-2-(5-keto-6-octene-dioyl) phosphatidylcholine (KOdia-PC), was added to the starting organic phase. The chemical–physical and technological characterization of the obtained nanoparticles demonstrated that: both the drug loading (DL%) and the entrapment efficiency (EE%) entrapped drug are high; the entrapped drug is in the amorphous state, protected from degradation and slowly released from the polymeric matrix; and the KOdia-PC is on the nanoparticle surface (KP-Nano). The biological characterization demonstrated that both systems are quickly internalized by macrophages while maintaining the activity of the drug. In vitro studies demonstrated that the effect of KP-Nano Rapa-loaded, in reducing the amount of the Phospo-Ser757-ULK1 protein through the inhibition of the mammalian target of rapamycin (mTOR), is comparable to that of the free drug.

Development of a novel rapamycin loaded nano- into micro-formulation for treatment of lung inflammation

“…Poly-ɛ-caprolactone-succinate (SUCC-PCL) was synthesized and characterized as reported elsewhere [27,30].…”

“…A modified synthetic procedure was followed to synthesize PHEA-g-RhB-g-SUCC-PCL graft copolymer with proper derivatization degree (DD%) [30]. Briefly, to an organic PHEA-g-RhB dispersion in a-DMF (33 mg/mL), DEA was added as catalyst according to R 2 = 0.3 that is the molar ratio between DEA and those of repeating units (RUs) of PHEA-g-RhB carrying hydroxyl groups.…”

“…Size and ζ potential measurements Hydrodynamic diameter (Z-average), polydispersity index (PDI), and ζ potential of each sample were determined by using a Malvern Zetasizer Nano ZSP instrument (Malvern Instrument, Malvern, UK), a He-Ne laser at λ = 632.8 nm, and at a fixed scattering angle of 175°. Each sample, freshly prepared or dispersed in ultrapure water, was analyzed at 25 °C [30]. Each measurement was repeated in triplicate.…”

Nano-structured myelin: new nanovesicles for targeted delivery to white matter and microglia, from brain-to-brain

“…For loading measurements, weighted amounts of samples were dispersed in DMF and drugs were quantified by High-performance liquid chromatography (HPLC) methods using a reversed-phase C 18 Luna column (5 ​μm of 250 ​mm x 4.6 ​mm internal diameter; Phenomenex). In particular, Dox HCl was quantified by eluting with a mobile phase composed of methanol and ammonium phosphate 10 ​mM, pH 4.5 (70:30 v/v) with a flow rate of 0.6 ​ml/min at 260 ​nm [ 38 ]. Instead, zileuton and sirolymus were quantified using a mobile phase of water/methanol (30/70, v/v) using a flow rate of 0.6 ​ml/min, at 260 ​nm [ 39 , 40 ].…”

Stimuli-Responsive Poly(aspartamide) Derivatives and Their Applications as Drug Carriers

“…For side chain-modified poly(aspartic acid)based polymers, they can generally be prepared by the aminolysis reaction of PSI. For example, a side chain-modified poly(aspartamide) (PASPAm) derivative, α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA), can be obtained by the aminolysis reaction between ethanolamine and PSI, and has been further modified and intensively studied as scaffolds [9], siRNA delivery systems [10,11] and drug carriers (e.g., hydrogel, nanoparticles) [12][13][14][15][16]. For the block copolymers containing poly(aspartic acid)-based segment, they usually can be synthesized by ROP of BLA-NCA.…”