in terms of LPS and LTA neutralization and lower pro-inflammatory activity. In addition, the acetylated and amidated version of this peptide shows no toxicity and displays higher or equal antimicrobial activity compared to LL-37.
To design stable biodegradable micelles with a size smaller than 20 nm, the self-assembly of
methoxypoly(ethylene glycol)-b-oligocaprolactones (mPEG-b-OCLs), and the effect of OCL block length and
terminal derivatization with an aromatic group were studied. The studied oligomers consisted of an mPEG block
with a molecular weight of 750 Da and a monodisperse OCL block of 1−7 units with a hydroxyl end group that
was either unmodified, benzoylated or naphthoylated. They were prepared by preparative HPLC of the polydisperse
block oligomers. Differential scanning calorimetry demonstrated that the two blocks were phase separated and
crystallized separately. These block oligomers formed small and almost monodisperse oligomeric micelles with
a hydrodynamic diameter of 8−15 nm, which could be tailored by the size of the hydrophobic block. The critical
aggregation concentration (CAC) of the unmodified mPEG-b-OCLs was 0.03−4 mg/mL, and it decreased with
increasing length of the OCL chain. End group modification resulted in an extensive reduction of the CAC to
values as low as 0.003 mg/mL. This is expected to result in a better stability of these oligomeric micelles toward
dilution upon intravenous administration, which makes these modified mPEG-b-OCLs very promising candidates
for drug delivery purposes.
A potent anti-vascular endothelial growth factor (VEGF) biologic and a compatible delivery system were co-evaluated for protection against wet age-related macular degeneration (AMD) over a 6month period following a single intravitreal (IVT) injection. The anti-VEGF molecule is dimeric, containing two different anti-VEGF domain antibodies (dAb) attached to a human IgG1 Fc region: a dual dAb. The delivery system is based on microparticles of PolyActive™ hydrogel co-polymer. The molecule was evaluated both in vitro for potency against VEGF and in ocular VEGF-driven efficacy modelsin vivo. The dual dAb is highly potent, showing a lower IC50 than aflibercept in VEGF receptor binding assays (RBAs) and retaining activity upon release from microparticles over 12 months in vitro. Microparticles released functional dual dAb in rabbit and primate eyes over 6 months at sufficient levels to protect Cynomolgus against laser-induced grade IV choroidal neovascularisation (CNV). This demonstrates proof of concept for delivery of an anti-VEGF molecule within a sustained-release system, showing protection in a pre-clinical primate model of wet AMD over 6 months. Polymer breakdown and movement of microparticles in the eye may limit development of particle-based approaches for sustained release after IVT injection.
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