Repeated intravitreal injections of steroids and anti-VEGF agents in the treatment of macular edema, pose potential post-surgical problems. Risk of drug precipitation due to poor solubility;and short vitreal half life upon intravitreal injection are the key deterrents in their delivery. Therefore the broad, long-term objective of this renewal grant application is to develop novel transscleral delivery strategies and to provide non-invasive therapy for macular edema. We propose to combine the prodrug approach with a novel polymeric drug delivery strategy by incorporating these prodrugs into biodegradable surface modified PLGA nanoparticles and thermosensitive PLGA-PEG-PLGA gel. This novel delivery system may provide added stability to steroids and bevacizumab and six-month sustained delivery from a single episcleral administration. Therefore the specific aims of this new grant application are: (1) to determine transscleral permeability of steroids (dexamethasone and prednisolone) and anti-VEGF monoclonal antibody (bevacizumab) (i) alone (ii) encapsulated in unmodified and surface modified nanoparticles (biotin transporter/folate receptor targeted) and (iii) nanoparticles suspended in the thermosensitive gel, using in vitro (ARPE-19 cell line) and ex vivo (isolated sclera and RPE-choroid-sclera) models (2) to synthesize ester-peptide (Valine-, Valine-Valine-, Glycine-Valine-, and Tyrosine-Valine-) prodrugs of dexamethasone and prednisolone targeting peptide transporters present on the basal side of the RPE. We also aim to characterize the physicochemical properties i.e., aqueous solubility, octanol/water partition coefficient, buffer stability and biochemical pharmacology (bioreversion and metabolism) of these compounds in ocular fluids and tissue homogenates including retina/choroid, lens, iris-ciliary body, sclera, vitreous humor and aqueous humor (3) to determine enzymatic stability of steroids, their peptide prodrugs and bevacizumab (i) alone, (ii) encapsulated in unmodified and surface modified nanoparticles and (iii) nanoparticles suspended in the thermosensitive gel, utilizing ocular tissues homogenates i.e. sclera, retina/choroid/Bruch's membrane (4) to evaluate a series of peptide prodrugs of steroids, targeted towards peptide transporters present on the RPE for transscleral delivery (i) alone (ii) encapsulated in unmodified and surface modified nanoparticles and (iii) nanoparticles suspended in the thermosensitive gel using an in vitro (ARPE-19 cell line) and/or ex vivo (isolated sclera and RPE-choroid-sclera) models (5) to evaluate in vivo time and dose dependent ocular bioavailability of steroids and bevacizumab (i) alone (ii) encapsulated in unmodified and surface modified nanoparticles and (iii) nanoparticles suspended in a thermosensitive PLGA-PEG-PLGA gel, following subconjunctival administration, using ocular microdialysis technique in anesthetized and conscious rabbit model. PUBLIC HEALTH RELAVANCE: The broad, long-term objective of this renewal grant application is to develop novel transscleral delivery strategies and to provide non-invasive therapy of steroids (dexamethasone and prednisolone) and anti-VEGF antibody (bevacizumab) for the treatment of macular edema. We propose to combine the prodrug approach with a novel polymeric drug delivery strategy by incorporating these prodrugs into biodegradable surface modified PLGA nanoparticles and thermosensitive PLGA-PEG-PLGA gel. This novel delivery system may provide added stability to steroids and bevacizumab and six-month sustained delivery from a single episcleral administration.
| Mandal, Abhirup; Pal, Dhananjay; Agrahari, Vibhuti et al. (2018) Ocular delivery of proteins and peptides: Challenges and novel formulation approaches. Adv Drug Deliv Rev 126:67-95 |
| Agrahari, Vibhuti; Agrahari, Vivek; Mandal, Abhirup et al. (2017) How are we improving the delivery to back of the eye? Advances and challenges of novel therapeutic approaches. Expert Opin Drug Deliv 14:1145-1162 |
| Joseph, Mary; Trinh, Hoang M; Cholkar, Kishore et al. (2017) Recent perspectives on the delivery of biologics to back of the eye. Expert Opin Drug Deliv 14:631-645 |
| Mandal, Abhirup; Bisht, Rohit; Rupenthal, Ilva D et al. (2017) Polymeric micelles for ocular drug delivery: From structural frameworks to recent preclinical studies. J Control Release 248:96-116 |
| Mandal, Abhirup; Cholkar, Kishore; Khurana, Varun et al. (2017) Topical Formulation of Self-Assembled Antiviral Prodrug Nanomicelles for Targeted Retinal Delivery. Mol Pharm 14:2056-2069 |
| Agrahari, Vibhuti; Agrahari, Vivek; Hung, Wei-Ting et al. (2016) Composite Nanoformulation Therapeutics for Long-Term Ocular Delivery of Macromolecules. Mol Pharm 13:2912-22 |
| Patel, Sulabh P; Vaishya, Ravi; Patel, Ashaben et al. (2016) Optimization of novel pentablock copolymer based composite formulation for sustained delivery of peptide/protein in the treatment of ocular diseases. J Microencapsul 33:103-13 |
| Agrahari, Vibhuti; Mandal, Abhirup; Agrahari, Vivek et al. (2016) A comprehensive insight on ocular pharmacokinetics. Drug Deliv Transl Res 6:735-754 |
| Agrahari, Vibhuti; Agrahari, Vivek; Mitra, Ashim K (2016) Nanocarrier fabrication and macromolecule drug delivery: challenges and opportunities. Ther Deliv 7:257-78 |
| Cholkar, Kishore; Gilger, Brian C; Mitra, Ashim K (2016) Topical delivery of aqueous micellar resolvin E1 analog (RX-10045). Int J Pharm 498:326-34 |
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