Improved intervention of atherosclerosis and cardiac hypertrophy through biodegradable polymer-encapsulated delivery of glycosphingolipid inhibitor

Abstract

D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), a glycosphingolipid synthesis inhibitor, holds promise for the treatment of atherosclerosis and cardiac hypertrophy but rapid in vivo clearance has severely hindered translation to the clinic. To overcome this impediment, we used a materials-based delivery strategy wherein D-PDMP was encapsulated within a biodegradable polymer composed of poly ethylene glycol (PEG) and sebacic acid (SA). PEG-SA was formulated into nanoparticles that were doped with 125I-labeled PEG to allow in vivo bio-distribution and release kinetics of D-PDMP to be determined by using γ-scintigraphy and subsequently, by mass spectrometry. Polymer-encapsulation increased the residence time of D-PDMP in the body of a treated mouse from less than one hour to at least four hours (and up to 48 h or longer). This substantially increased in vivo longevity provided by polymer encapsulation resulted in an order of magnitude gain in efficacy for interfering with atherosclerosis and cardiac hypertrophy in apoE−/− mice fed a high fat and high cholesterol (HFHC) diet. These results establish that D-PDMP encapsulated in a biodegradable polymer provides a superior mode of delivery compared to unconjugated D-PDMP by way of increased gastrointestinal absorption and increased residence time thus providing this otherwise rapidly cleared compound with therapeutic relevance in interfering with atherosclerosis, cardiac hypertrophy, and probably other diseases associated with the deleterious effects of abnormally high glycosphingolipid biosynthesis or deficient catabolism.

Myriocin and d-PDMP ameliorate atherosclerosis in ApoE−/− mice via reducing lipid uptake and vascular inflammation

“…The nearly normal serum TG levels in all groups could probably explain why all treatments had no effects on TG metabolism. Besides, the medication time may partly explain the different effects on LDL-C levels, as according to their reported data, 24-or 16-weeks d-PDMP treatment approximately reduced serum LDL-C levels by 70% or 30% [10,23]. But above all, the data do suggest that d-PDMP could inhibit atherosclerosis, although serum cholesterols were not reduced below some certain threshold.…”

Medial calcification in the arterial wall of smooth muscle cell‐specific Smpd1 transgenic mice: A ceramide‐mediated vasculopathy

“…PDMP, a ceramide analogue, is a promising target for preventing cardiovascular diseases such as atherosclerosis and cardiac hypertrophy 30,31 and for suppressing osteoclastogenesis by inhibiting glycosphingolipid synthesis. 31,32 Ode et al 33 findings demonstrated that PDMP reduced osteoblastic proliferation and pre-osteoblastic cell differentiation by translocation of mTORC1 from late endosome/lysosome (LE/Ly) to the endoplasmic reticulum (ER), suggesting inhibition of mTORC1 activity. This inhibitory action of ceramide analogue allows normal lysosomal functioning or lysosomal activation and their fusion with MVBs.…”

Inhibition of glycosphingolipid synthesis reverses skin inflammation and hair loss in ApoE−/− mice fed western diet

“…Previously we found that the encapsulation of D-PDMP within a biopolymer, consisting of polyethylene glycol and sebacic acid, increased gastrointestinal absorption of D-PDMP, and increased its longevity in ApoE−/− mice from less than 1 hr, for the unconjugated D-PDMP, to ~48 hours 52 – 62 . Consequently, 1 mpk of BPD was equally efficacious as 10 mpk of free D-PDMP in decreasing LacCer levels in aortic tissue in ApoE−/− mice 37 .…”