Table 2.
Novel sustained anti-VEGF [Bevacizumab (Avastin™), Ranibizumab (Lucentis™) and Aflibercept (Eylea™)] delivery systems tested in in vivo models.
| Technology and year of publication | Drug loaded | Phase of development | Bioactivity testing | Biocompatibility testing | Sustained release testing and duration | Drug encapsulation characteristics (encapsulation efficiency and loading efficiency) | Optical clarity |
|---|---|---|---|---|---|---|---|
| Polymeric nanoparticle (NP) and microparticle (MP) technology | |||||||
| Drug-loaded PLGA/PCADK microspheres (2019) [60] | Bevacizumab (Avastin™) |
Pre-clinical • SR tested In vivo • Biocomp tested in vivo |
In vitro bioactivity proven on chorioallantoic membrane assay |
New Zealand white rabbits • Mild inflammatory cells on histology |
New Zealand white rabbits IVT • At least 50 days |
EE: 35% for 20% PCADK content | Not commented |
| Drug-loaded mesoporous silica nanoparticles (2019) [62] | Bevacizumab (Avastin™) |
Pre-clinical • SR tested in vivo • Biocomp tested in vivo • Bioactivity tested in vivo |
Proven on oxygen-induced retinopathy mouse model |
C57BL/6J mice • NIL histological changes • NIL significant difference in ERG findings with control |
C57BL/6J mice IVT • Half-life of 8.7 days as opposed to 5.3 days in direct injections |
EE: 85.3% | Not commented |
| Drug-loaded PLGA microspheres (2015) [63] | Bevacizumab (Avastin™) |
Pre-clinical • SR tested in vivo |
NIL bioactivity testing | NIL biocompatibility results |
New Zealand albino rabbit IVT • At least 42 days |
EE: 49% LE: 9.8% |
Not commented |
| Drug-loaded albuminated PLGA nanoparticles (2015) [61] | Bevacizumab (Avastin™) |
Pre-clinical • SR tested in vivo • Biocomp tested in vivo |
NIL bioactivity testing |
New Zealand albino rabbits • NIL inflammation on histology • NIL changes to ERG |
New Zealand albino rabbit IVT • At least 2 months |
EE: 84% LE: 7.4% |
Not commented |
| Drug-linked chitosan nanoparticles (2014) [58] | Bevacizumab (Avastin™) |
Pre-clinical • SR tested in vivo • Biocomp tested in vivo |
RT PCR assay testing of VEGF mRNA expression in diabetic rat retina | NIL biocompatibility results |
Sprague Dawley diabetic rats • At least 8 weeks |
Not commented | No commented |
| Drug-loaded PLA nanoparticles in porous PLGA microparticles (2013) [64] | Bevacizumab (Avastin™) |
Pre-clinical • SR tested in vivo |
NIL bioactivity testing | NIL biocompatibility results |
Rat model IVT • At least 4 months |
NIL LE or EE data | Not commented |
| Liposome technology | |||||||
| Drug-loaded multi-vesicular liposomes (2018) [65] | Bevacizumab (Avastin™) |
Pre-clinical • SR tested in vivo • Bioactivity tested in vivo |
Proven on laser-induced choroidal neovascularisation Brown-Norway rat model | NIL biocompatibility results |
New Zealand white rabbit IVT • At least 56 days |
EE: 80.6% • LE: not stated |
Not commented |
| Drug-loaded egg phosphatidylcholine:cholesterol (liposome) (2009) [68] | Bevacizumab (Avastin™) |
Pre-clinical • SR tested in vivo |
NIL bioactivity testing | NIL biocompatibility results |
New Zealand albino rabbit IVT • At least 42 days (concentration of drug still five times higher than Bevacizumab solution) |
EE: 45.5% LE: not stated |
Not commented |
| Hydrogel technology | |||||||
| Drug-loaded PLGA microspheres suspended in a PEG-PLLA-DA/NIPAAm hydrogel (2019) [99, 103, 104] | Ranibizumab (Lucentis™)Aflibercept (Eylea™) |
Pre-clinical • SR tested in vivo • Biocomp tested in vivo • Bioactivity tested in vivo |
Proven on laser-induced choroidal neovascularisation Long-Evans rat model |
Long-Evans Rat model • Small transient increase in intraocular pressure after injection • NIL changes on ERG |
Long-Evans rat IVT • At least 12 weeks |
Ranibizumab microsphere: • EE in microsphere: 45.6% • EE of microsphere in gel: 74.2% • Aflibercept microsphere • EE in microsphere: 52% • EE of microsphere in gel: 70.9% Aflibercept |
Not commented |
| OTX-IVT (anti-VEGF intravitreal hydrogel implant) (2017) [108] | Bevacizumab (Avastin™) |
Pre-clinical • SR tested in vivo • Bioactivity tested in vivo • Biocomp tested in vivo • Clinical trials have commenced for tyrosine kinase inhibitor (TKI) loaded-gel (ClinicalTrial.gov ID: NCT03630315) |
Proven on rabbit VEGF challenge model |
Rabbit VEGF challenge model • NIL evidence of inflammation |
Rabbit IVT VEGF challenge model • At least 12 weeks |
Not commented | Compact depot which does not cause blurring of vision |
| Drug-loaded PLGA-PEG-PLGA hydrogel (2015) [100] | Bevacizumab (Avastin™) |
Pre-clinical • SR tested in vivo • Biocomp tested in vivo |
NIL neovascularisation models tested |
Sprague Dawley rats • NIL signs of inflammation clinically and histologically • NIL changes to retinal thickness on OCT • NIL changes on ERG at 4 or 8 weeks |
Sprague Dawley rats IVT • At least 6 weeks |
1.25% drug content gel created | Not commented |
| Drug-loaded vinylsulfone functionalised hyaluronic acid (HV-VS) and thiolated dextran (Dex-SH) hydrogel (2015) [92] |
Bevacizumab (Avastin™) |
Pre-clinical • SR tested in vivo • Biocomp tested in vivo |
In vitro bioactivity proven on ELISA assay with VEGF-capture protein |
New Zealand white rabbits • Transient increase in intraocular pressure after injection. • NIL observed abnormalities on BIO • NIL changes on ERG • NIL signs of inflammation histologically |
New Zealand white rabbits IVT • At least 6 months (drug concentration 107 times higher than eyes receiving bolus injections) |
12.5 mg/ml drug content gel created • 40 µl gel injected |
Transparent as viewed on the BIO |
| Drug-loaded silk hydrogel (2015) [91] |
Bevacizumab (Avastin™) |
Pre-clinical • SR tested in vivo • Biocomp tested in vivo |
In vitro bioactivity proven on ELISA assay with VEGF-capture protein |
Dutch-belted rabbits • Minimal inflammation noted clinically in AC/posterior segment after 1 month |
Dutch-belted rabbits IVT • At least 3 months |
Standard dose hydrogel • 1.25 mg in 50 µl gel High-dose hydrogel • 5 mg in 50 µl gel |
Not commented |
| Drug-loaded poly (ethylene glycol)-poly-(serinol hexamethylene urethane) (ESHU) hydrogel (2014) [98, 101] |
Bevacizumab (Avastin™) |
Pre-clinical • SR tested in vivo • Biocomp tested in vivo |
NIL neovascularisation models tested |
New Zealand white rabbit • NIL evidence of inflammation clinically or on histology • NIL change in IOP post injection |
New Zealand white rabbits IVT • At least 9 weeks (drug conc 4.7 times higher than eyes receiving bolus injections) |
Not commented | Not commented |
| Non-biodegradable implant technology | |||||||
| Port delivery system (PDS) (2016) [56] |
Ranibizumab (Lucentis™) |
Clinical • Phase III trials (Pivotal) |
Ranibizumab-responsive n-AMD patients • 100 mg/ml PDS produces similar visual acuity as monthly injections |
Ranibizumab-responsive n-AMD patients • PDS arm had more adverse events than monthly injection group |
Average refill time • Every 16 months |
Not applicable | Not applicable |
| Replenish Posterior Micropump (PMP) (2014) [55] |
Ranibizumab (Lucentis™) |
Clinical • Phase I trials (Feasibility) |
Diabetic macular oedema patients • Decrease in central foveal thickness at 2nd week |
Diabetic macular oedema patients • NIL serious adverse events or visual acuity loss noted |
Trial lasted for 3-month period | Not applicable | Not applicable |
Encapsulation efficiency (EE%) = (Total drug added−free non-entrapped drug)/total drug added. Loading efficiency (LE%) = Amount of total entrapped drug/total nanoparticle weight.
SR sustained release, OTX ocular therapeutix, Biocomp biocompatibility, IVT intravitreal injection, IOP intraocular pressure, EE encapsulation efficiency, LE loading efficiency, PLLA poly (l-lactic acid), NIPAAm N-isopropylacrylamide.