The 599 peptide has been previously shown to effectively deliver small interfering RNAs (siRNAs) to cancer cells, inducing targeted-oncogene silencing, with a consequent inhibition of tumor growth. Although effective, this study was undertaken to advance the 599 peptide siRNA-carrier design through L/D-amino acid stereochemical modifications. Consequently, 599 was modified to generate eight different peptide variants, incorporating either different stereochemical patterns of L/D-amino acids or a specific D-amino acid substitution. Upon analysis of the variants, it was observed that these modifications could, in some instances, increase/decrease the binding, nuclease/serum stability, and complex release of siRNAs, as well as influence the gene-silencing efficiencies of the complex. These modifications were also found to affect cellular uptake and intracellular localization patterns of siRNA cargo, with one particular variant capable of mediating binding of siRNAs to specific cellular projections, identified as filopodia. Interestingly, this variant also exhibited the most enhanced gene silencing in comparison to the parent 599 peptide, thus suggesting a possible connection between filopodia binding and enhanced gene silencing. Together, these data demonstrate the utility of peptide stereochemistry, as well as the importance of a key D-amino acid modification, in advancing the 599 carrier design for the enhancement of gene silencing in cancer cells.

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Purpose: We report a rare case of neurosensory retinal detachment (RD) in the setting of a giant retinal pigment epithelium (RPE) tear. Methods: A 58-year-old man presented with a macula-involving RD in the left eye. Exam revealed a neurosensory detachment inferiorly and RPE abnormalities temporally. Optical coherence tomography showed a large RPE tear and detachment in the temporal macula contiguous with a neurosensory RD. Results: No clear etiology was identified and failure of conservative management led to vitrectomy with RD repair. Follow-up intravenous fluorescein angiography 3 months postoperatively showed a large RPE window defect. Conclusions: RPE tears are common; however, concomitant neurosensory RD is rare. A thorough workup to determine treatable causative factors is necessary; in the event of idiopathic diagnosis, close follow-up is necessary to determine the need for surgery. Pars plana vitrectomy, external drainage of subretinal fluid, endolaser, and 5000-centistoke silicone oil placement were successful in this patient.