PMID- 30295090
OWN - NLM
STAT- MEDLINE
DCOM- 20200501
LR  - 20220409
IS  - 1460-2202 (Electronic)
IS  - 0271-3683 (Print)
IS  - 0271-3683 (Linking)
VI  - 44
IP  - 3
DP  - 2019 Mar
TI  - Biodegradable Microsphere-Hydrogel Ocular Drug Delivery System for Controlled and 
      Extended Release of Bioactive Aflibercept In Vitro.
PG  - 264-274
LID - 10.1080/02713683.2018.1533983 [doi]
AB  - PURPOSE: Current standard of care for neovascular eye diseases require repeated 
      intravitreal bolus injections of anti-vascular endothelial growth factors 
      (anti-VEGFs). The purpose of this study was to validate a degradable 
      microsphere-thermoresponsive hydrogel drug delivery system (DDS) capable of 
      releasing bioactive aflibercept in a controlled and extended manner for 6 months. 
      MATERIALS AND METHODS: The DDS was fabricated by suspending aflibercept-loaded 
      poly(lactic-co-glycolic acid) microspheres within a biodegradable poly(ethylene 
      glycol)-co-(l-lactic acid) diacrylate/N-isopropylacrylamide (PEG-PLLA-DA/NIPAAm) 
      thermoresponsive hydrogel. Encapsulation efficiency of DDSs and in vitro release 
      profiles were characterized by iodine-125 radiolabeled aflibercept. The 
      degradation of hydrogel was determined by dry weight changes. The cytotoxicity 
      from degraded DDS byproducts was investigated by quantifying cell viability using 
      LIVE/DEAD(R) assay. In addition, dot blot and enzyme-linked immunosorbent assay 
      were used to determine the bioactivity of released drug. Finally, morphology of 
      microspheres and hydrogel were investigated by cryo-scanning electron microscopy 
      before and after thermal transformation. RESULTS: The microsphere-hydrogel DDS 
      was capable of releasing bioactive aflibercept in a controlled and extended 
      manner for 6 months. The amount and rate of aflibercept release can be controlled 
      by both the cross-linker concentration and microspheres load amount. The initial 
      burst (release within 24 h) was from 37.35 +/- 4.92 to 74.56 +/- 6.16 microg (2 and 3 mM 
      hydrogel, each loaded with 10 and 20 mg/ml of microspheres, respectively), 
      followed by controlled drug release of 0.07-0.15 microg/day. Higher PEG-PLLA-DA 
      concentration (3 mM) degraded faster than the lower concentration (2 mM). No 
      significant cytotoxicity from degraded DDS byproducts was found for all 
      investigated time points. Bioactivity of released drug was maintained at 
      therapeutic level over entire release period. CONCLUSIONS: The 
      microsphere-hydrogel DDS is safe and can deliver bioactive aflibercept in a 
      controlled manner. This may provide a significant advantage over current bolus 
      injection therapies in the treatment of ocular neovascularization.
FAU - Liu, Wenqiang
AU  - Liu W
AD  - a Biomedical Engineering , Illinois Institute of Technology , Chicago , Illinois 
      , USA.
FAU - Lee, Bao-Shiang
AU  - Lee BS
AD  - b Research Resource Center , University of Illinois at Chicago , Chicago , 
      Illinois , USA.
FAU - Mieler, William F
AU  - Mieler WF
AD  - c Ophthalmology and Visual Sciences , University of Illinois at Chicago , Chicago 
      , Illinois , USA.
FAU - Kang-Mieler, Jennifer J
AU  - Kang-Mieler JJ
AD  - a Biomedical Engineering , Illinois Institute of Technology , Chicago , Illinois 
      , USA.
LA  - eng
GR  - R15 EY025434/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Validation Study
DEP - 20181019
PL  - England
TA  - Curr Eye Res
JT  - Current eye research
JID - 8104312
RN  - 0 (Acrylamides)
RN  - 0 (Acrylates)
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Delayed-Action Preparations)
RN  - 0 (Hydrogels)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (poly(ethylene glycol)-co-(L-lactic acid)diacrylate)
RN  - 15C2VL427D (aflibercept)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - B7GFF17L9U (N-isopropylacrylamide)
RN  - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)
SB  - IM
MH  - *Absorbable Implants
MH  - Acrylamides/chemistry
MH  - Acrylates/chemistry
MH  - Angiogenesis Inhibitors/*administration & dosage/pharmacokinetics
MH  - Animals
MH  - Cell Survival
MH  - Cells, Cultured
MH  - Delayed-Action Preparations
MH  - *Drug Delivery Systems
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Human Umbilical Vein Endothelial Cells/drug effects
MH  - Humans
MH  - Hydrogels/*chemistry
MH  - Immunoblotting
MH  - Microspheres
MH  - Polyethylene Glycols/chemistry
MH  - Receptors, Vascular Endothelial Growth Factor/*administration & dosage
MH  - Recombinant Fusion Proteins/*administration & dosage/pharmacokinetics
MH  - Vascular Endothelial Growth Factor A/antagonists & inhibitors
PMC - PMC7216294
MID - NIHMS1585180
OTO - NOTNLM
OT  - Anti-VEGF delivery
OT  - bioactivity
OT  - intravitreal injection
OT  - neovascularization
OT  - thermoresponsive hydrogel
COIS- Disclosure statement No potential conflict of interest was reported by the 
      authors.
EDAT- 2018/10/09 06:00
MHDA- 2020/05/02 06:00
PMCR- 2020/05/12
CRDT- 2018/10/09 06:00
PHST- 2018/10/09 06:00 [pubmed]
PHST- 2020/05/02 06:00 [medline]
PHST- 2018/10/09 06:00 [entrez]
PHST- 2020/05/12 00:00 [pmc-release]
AID - 10.1080/02713683.2018.1533983 [doi]
PST - ppublish
SO  - Curr Eye Res. 2019 Mar;44(3):264-274. doi: 10.1080/02713683.2018.1533983. Epub 
      2018 Oct 19.