2 research outputs found
Acid-Labile mPEGâVinyl Etherâ1,2-Dioleylglycerol Lipids with Tunable pH Sensitivity: Synthesis and Structural Effects on Hydrolysis Rates, DOPE Liposome Release Performance, and Pharmacokinetics
A family of 3-methoxypolyÂ(ethylene glycol)âvinyl
etherâ1,2-dioleylglycerol
(mPEG-VE-DOG) lipopolymer conjugates, designed on the basis of DFT
calculations to possess a wide range of proton affinities, was synthesized
and tested for their hydrolysis kinetics in neutral and acidic buffers.
Extruded âŒ100 nm liposomes containing these constructs in â„90
mol % 1,2-dioleoyl-<i>sn</i>-glycero-3-phosphoethanolamine
(DOPE) produced dispersions that retained their calcein cargo for
more than 2 days at pH 7.5, but released the encapsulated contents
over a wide range of time scales as a function of the electronic properties
of the vinyl ether linkage, the solution pH, and the mPEG-VE-DOG composition
in the membrane. The <i>in vivo</i> performance of two different
90:10 DOPE:mPEG-VE-DOG compositions was also evaluated for blood circulation
time and biodistribution in mice, using <sup>125</sup>I-tyraminylinulin
as a label. The pharmacokinetic profiles gave a <i>t</i><sub>1/2</sub> of 7 and 3 h for 90:10 DOPE:ST302 and 90:10 DOPE:ST502,
respectively, with the liposomes being cleared predominantly by liver
and spleen uptake. The behavior of these DOPE:mPEG-VE-DOG formulations
is consistent with their relative rates of vinyl ether hydrolysis,
i.e., the more acid-sensitive mPEG-VE-DOG derivatives produced faster
leakage rates from DOPE:mPEG-VE-DOG liposomes, but decreased the blood
circulation times in mice. These findings suggest that the vinyl ether-based
PEGâlipid derivatives are promising agents for stabilizing
acid-sensitive DOPE liposomes to produce formulations with <i>a priori</i> control over their pH responsiveness <i>in
vitro</i>. Our data also suggest, however, that the same factors
that contribute to enhanced acid sensitivity of the DOPE:mPEG-VE-DOG
dispersions are also likely responsible for their reduced pharmacokinetic
profiles
Tumor Selective Silencing Using an RNAi-Conjugated Polymeric Nanopharmaceutical
Small
interfering RNA (siRNA) therapeutics have potential advantages
over traditional small molecule drugs such as high specificity and
the ability to inhibit otherwise âundruggableâ targets.
However, siRNAs have short plasma half-lives <i>in vivo</i>, can induce a cytokine response, and show poor cellular uptake.
Formulating siRNA into nanoparticles offers two advantages: enhanced
siRNA stability against nuclease degradation beyond what chemical
modification alone can provide; and improved site-specific delivery
that takes advantage of the enhanced permeability and retention (EPR)
effect. Existing delivery systems generally suffer from poor delivery
to tumors. Here we describe the formation and biological activity
of polymeric nanopharmaceuticals (PNPs) based on biocompatible and
biodegradable polyÂ(lactic-<i>co</i>-glycolic acid) (PLGA)
conjugated to siRNA via an intracellular cleavable disulfide linker
(PLGAâsiRNA). Additionally, these PNPs contain (1) PLGA conjugated
to polyethylene glycol (PEG) for enhanced pharmacokinetics of the
nanocarrier; (2) a cation for complexation of siRNA and charge compensation
to avoid high negative zeta potential; and (3) neutral polyÂ(vinyl
alcohol) (PVA) to stabilize the PNPs and support the PEG shell to
prevent particle aggregation and protein adsorption. The biological
data demonstrate that these PNPs achieve prolonged circulation, tumor
accumulation that is uniform throughout the tumor, and prolonged tumor-specific
knockdown. PNPs employed in this study had no effect on body weight,
blood cell count, serum chemistry, or cytokine response at doses >10
times the effective dose. PNPs, therefore, constitute a promising
solution for achieving durable siRNA delivery and gene silencing in
tumors