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Hybrid or recombinant protein-polymers, peptide-based biomaterials, and antibody-targeted therapeutics are widely explored for various ocular conditions and vision correction. They have been noted for their potential biocompatibility, potency, adaptability, and opportunities for sustained drug delivery. Unique to peptide and protein therapeutics, their production by cellular translation allows their precise modification through genetic engineering. To a greater extent than drug delivery to other systems, delivery to the eye can benefit from the combination of locally-targeted administration and protein-based specificity. Consequently, a range of delivery platforms and administration methods have been exploited to address the ocular delivery of peptide and protein biomaterials. This review discusses a sample of preclinical and clinical opportunities for peptide-based drug delivery to the eye.

Achievement of a high dose of drug in the tumor while minimizing its systemic side effects is one of the important features of an improved drug delivery system. Thus, developing responsive carriers for site-specific delivery of chemotherapeutic agents has become a main goal of research efforts. One of the known hallmarks of cancerous tumors is hypoxia, which offers a target for selective drug delivery. The stimuli-sensitive micellar system developed by us, (PEG-azobenzene-PEI-DOPE (PAPD) has proven to be effective in vitro. The proposed construct developed, PAPD, contains an azobenzene group as a hypoxia-sensitive moiety that triggers the shedding of the PEG layer from the nanoparticle surface under conditions of hypoxia to improve cellular uptake. Using microfluidics, we show significantly improved cellular association and penetration under hypoxia in both single cells and in a 3D tumor model. Employing an in vivo model, we demonstrate slower tumor growth that did not induce systemic side effects, including weight loss in an experimental animal model, when compared to the free drug treatment. This complex-in-nature but simple-in-design system for the simultaneous delivery of siRNA to silence the P-glycoprotein and doxorubicin with active tumor targeting and proven therapeutic efficacy represents a universal platform for the delivery of other hydrophobic chemotherapeutic agents and siRNA molecules which can be further modified.

Recently, it has been discovered that the PEG layer on nanoparticle surface can create steric hindrance, preventing efficient cellular uptake of PEGylated nanoparticles. Thus, it would be ideal to have a nanoparticle system that sheds the PEG layer upon reaching the tumor microenvironment. Hypoxia, which is a hallmark of cancerous tumors, can be used as a trigger to shed the PEG layer from the nanoparticle surface. In this study, a hypoxia-sensitive PEG-azobenzene-PEI-DOPE (PAPD) construct, with an azobenzene group as a hypoxia-sensitive moiety, was prepared. The feasibility of co-delivering Doxorubicin (Dox) and anti-P-gp siRNA (siPgp) using the PAPD nanoparticles was evaluated in monolayers of the Adriamycin-resistant human ovarian cancer cell line, A2780 ADR, and in 3D spheroids of the multidrug-resistant human breast cancer cell line, MCF7 ADR. Under hypoxic conditions, the PAPD nanoparticles showed up to a 60% increase in cellular uptake by monolayers and a significantly greater tumor penetration in a spheroid model. siPgp, when delivered using PAPD nanoparticles, showed up to a 60% P-gp downregulation under hypoxic conditions. The combination of siPgp and Dox delivered using PAPD nanoparticles led to an 80% cytotoxicity in cell monolayers and 20% cytotoxicity in spheroids under hypoxic conditions. In this research, a novel hypoxia-sensitive nanoparticle system was developed that demonstrated improved delivery of an encapsulated cargo and augmented cytotoxicity on multidrug-resistant cancer cells under hypoxic conditions.

Folic acid is often used for active targeting of tumor cells to enhance therapeutic outcomes. Here, folic acid was conjugated with chitosan and folate-conjugated chitosan-lipid hybrid nanoparticles were prepared by ionic gelation method using anionic lipid. These nanoparticles were in size range of 200 to 400 nm with spherical shape. In vitro drug release data suggested a sustained release of cisplatin. The therapeutic efficacy of the folate-conjugated hybrid nanoparticles was evaluated in SK-OV-3, A2780 and MCF-7 cancer cell lines. A significant increase in cytotoxicity was observed with folate targeted LPHNPs compared to non-targeted LPHNPs. Significantly enhanced cellular uptake and cell cycle arrest resulting from folate-targeted nanoparticles were confirmed using fluorescence microscopy and flow cytometry. The therapeutic efficacy and tumor penetration were further evaluated in 3D spheroid tumor models. These studies suggest that folate-conjugated lipid-chitosan nanoparticles could enhance therapeutic activity and may represent a promising platform for active targeting of tumor cells.