Cell-Penetrating Peptides for Targeted Delivery of Anti-VEGF Agents in Ocular Diseases
Somayeh Piroozmand1 , Zahra-Soheila Soheili1 *, Saman Hosseinkhani2 , Shahram Samiei3
- Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
Abstract: Cell-penetrating peptides (CPPs), also referred to as protein-transduction domains (PTDs), have emerged as a potent non-viral strategy to enhance drug delivery, particularly for anti-VEGF molecules in ocular diseases such as age-related macular degeneration (AMD) and diabetic retinopathy. These short peptides facilitate the translocation of therapeutic agents across cellular membranes while preserving their functional integrity. Critical factors in the design of CPPs include peptide sequence, structure, internalization efficiency, endosomal escape mechanisms, stability, and toxicity. By reducing systemic exposure and drug-associated side effects, CPPs minimize the risks typically associated with high-dose treatments.
Methods: Ocular drug delivery is inherently challenging due to anatomical and physiological barriers, including the blood-aqueous and blood-retina barriers, which impede drug access to target tissues. CPPs address these challenges by enhancing drug bioavailability and transport across these barriers via non-invasive or minimally invasive routes, such as topical applications and intravitreal injections. Notable CPPs evaluated for ocular applications include VP22, HIV-TAT, peptide for ocular delivery (POD), and nucleolin-binding peptide (NBP).
Results: POD has demonstrated efficacy in delivering both small and large molecules to the posterior eye segment, successfully targeting the retinal pigment epithelium (RPE), photoreceptors, ganglion cells, sclera, and choroid through topical administration.
Topical CPP-drug complexes, such as those involving bevacizumab and ranibizumab, have shown comparable effectiveness to intravitreal injections in reducing choroidal neovascularization (CNV) in animal models. In this study, we utilized a chimeric recombinant MiRGD peptide as a CPP, incorporating functional motifs such as histone H1, HIV glycoprotein 41 (Gp41), a nuclear localization signal (NLS) from simian virus 40 (SV40), and the cyclic Internalized RGD (iRGD) peptide to deliver the novel anti-angiogenic molecule htsFLT01 (hinge-truncated sFLT01) to the mouse retina. The results demonstrated significant inhibition of vascular development in the retinal capillary plexus layers.
Conclusion: In conclusion, CPP-based delivery systems offer a promising advancement for ocular therapeutics, combining improved efficacy, targeted delivery, and enhanced safety profiles to address unmet needs in the treatment of ocular diseases.
