# Steering the Clinical Translation of Delivery Systems for Drugs and Health Products
## 3 Poster Presentations
### Biocompatible Conjugates for Ocular Drug Delivery  
[PERSON] \({}^{1}\), [PERSON] \({}^{2}\), [PERSON] \({}^{3}\), [PERSON] \({}^{1}\), [PERSON] \({}^{3}\), [PERSON] \({}^{2}\), [PERSON] \({}^{1}\) and [PERSON] \({}^{1,*}\)  
\({}^{1}\) Department of Pharmaceutical and Pharmacological Sciences, University of Padua, via [PERSON]. Marzolo 5, 35122 Padua, Italy  
\({}^{2}\) Faculty of Pharmacy, Division of Pharmaceutical Biosciences, University of Helsinki, Viikinkaari 5 E, 00014 Helsinki, Finland  
\({}^{3}\) Department of Biomedical Engineering, Bio-Organic Chemistry, Eindhoven University of Technology, 5612 AZ Eindhoven, The Netherlands  
\({}^{*}\) Correspondence: [EMAIL_ADDRESS]  
Age related macular degeneration, an eye disease affecting the posterior segment of the eye, requires invasive techniques and repeated intravitreal injections for drug administration [16; 43; 44]. Reduced administration frequency is a major requirement to ensure a better patient compliance during treatment. We explored Pullulan anti-inflammatory drug conjugates as therapeutic systems to prolong residence time and control drug release in the vitreous after intravitreal administration.  
We have screened a few cleavable linkers for the conjugation of a model molecule, Rhodamine, to Pullulan. A hydrazone linker (HY) in Pull-Rh conjugate was selected based on its sustained release of Rh (50% of Rh, over 10 days under conditions mimicking the vitreous). The hydrophobic character of Rh induced the self-assembly of the conjugate into spherical particles with a size of 25 nm that possess a slow diffusivity in vitreous of about 0.02 \(\upmu\)m\({}^{2}\)/s derived by multiple tracking analysis. Moreover, the cytotoxicity and uptake studies investigated on Retinal Pigment Epithelial cells (ARPE-19) confirmed the biocompatibility of the carrier and highlighted a strong cellular uptake after 1 h incubation. The HY linker was then used to generate the conjugate with dexamethasone. 10% w/w of Dexa was conjugated to the Pull backbone. A fluorescent version of the conjugate was generated, Pull-BDP-Dexa, 5% w/w of Dexa and 1.3% w/w of BDP. The chemical identity of the conjugates was assessed by a combination of \({}^{1}\)H NMR, \({}^{13}\)C NMR, FT-IR, EA and Snyder assay. The conjugates underwent self-assembly into spherical particles with an average size of 320-370 nm (DLS). The morphology and shape of particles were assessed by TEM and NTA. The release study in PBS at pH 7.4 at 37 \({}^{\circ}\)C showed about 20% of Dexa release after 24 h. Ongoing studies will elucidate the release profile under vitreous mimicking conditions. Cytotoxicity studies of Pull-Dexa were performed on HeLa and ARPE-19 cells in a range of 5-600 \(\upmu\)M concentration of Dexa with Alamar blue assay, which showed the high biocompatibility of the conjugate. Cell uptake studies performed by incubating the same cell lines with Pull-BDP-Dexa for 24 h showed a significant association of the conjugates with cells.  
In summary, the synthesis of Dexa and BDP to Pull with HY linker were successfully set up and conjugates underwent an extensive characterization. The conjugates are promising because they possess slow diffusivity in the vitreous in which can anticipate higher residence time. Cytotoxicity and uptake study on ARPE-19 confirm that the conjugates are not toxic and efficient in associating to the cells. The future investigations will quantify cell association of the Pull-BDP-Dexa with cytofluorimetric analysis and confocal microscopy. Defined conditions mimicking the vitreous will be used to assess diffusivity of Dexa loaded particles by NTA.  
This project has received funding from the European Union's Horizon 2020 research and innovation program under the [PERSON] grant agreement N\({}^{\circ}\) 722717.  
The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.