Targeted Intraceptor Nanoparticle for Neovascular Macular Degeneration: Preclinical Dose Optimization and Toxicology Assessment

Zhang, Xiaohui; Bohner, Austin; Bhuvanagiri, Sai; Uehara, Hironori; Upadhyay, Ajay Kumar; Emerson, Lyska L.; Bondalapati, Sailaja; Muddana, Santosh Kumar; Fang, Daniel; Wen, Feng; Sandhu, Zoya; Hussain, Alya; Carroll, Lara; Tiem, Michelle; Archer, Bonnie; Kompella, Uday B.; Patil, Rajkumar V.; Ambati, Balamurali K.

doi:10.1016/j.ymthe.2017.01.014

Cited by 19 publications

(10 citation statements)

References 34 publications

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“…Integrins are essential in VEGF signaling in ocular NV. Although a few previous studies reported that RGD conjugation could actively target CNV, applying synthetic nanoparticles to conjugate with RGD or systemic administration of these particles diminished their clinical utility [ 33 , 34 , 35 , 36 ]. Here, we demonstrated that multiretinal cell-derived exosomes modified with an ASL system actively targeted CNV in a laser-induced CNV mouse model by promoting their uptake to overexpressed integrin

v at the site of CNV.…”

Section: Discussionmentioning

confidence: 99%

Intraocular RGD-Engineered Exosomes and Active Targeting of Choroidal Neovascularization (CNV)

Pollalis

Kim

Nair

et al. 2022

Cells

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Purpose: To assess the transretinal penetration of intravitreally injected retinal multicell-derived exosomes and to develop exosome-based active targeting of choroidal neovascularization (CNV) by bioengineering with ASL, which is composed of a membrane Anchor (BODIPY), Spacer (PEG), and targeting Ligands (cyclic RGD peptide). Methods: Retinal multicell-derived exosomes were recovered from a whole mouse retina using differential ultracentrifugation. Their size, number, and morphology were characterized using nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Exosome markers were confirmed using an exosome detection antibody array. Intravitreal injection of fluorescent (PKH-26)-labeled or engineered ASL exosomes (1 × 106 exosomes/μL) were given to the wild-type mouse or laser-induced CNV mouse model. Retinal uptake of exosomes was assessed by in vivo retinal imaging microscopy and histological staining with DAPI, GSA, and anti-integrin αv for retinal sections or choroid/RPE flat mounts. Active targeting of CNV was assessed by comparing retinal uptake between areas with and without CNV and by colocalization analysis of ASL exosomes with integrin αv within CNV. Staining with anti-F4/80, anti-ICAM-1, and anti-GFAP antibodies on retinal sections were performed to identify intracellular uptake of exosomes and immediate reactive retinal gliosis after exosome treatment. Results: An average of 2.1 × 109 particles/mL with a peak size of 140 nm exosomes were recovered. Rapid retinal penetration of intravitreally injected exosomes was confirmed by retinal imaging microscopy at 3 and 24 h post-injection. Intravitreally delivered PKH-26-labeled exosomes reached inner and outer retinal layers including IPL, INL, OPL, and ONL at 1 and 7 days post-injection. Intravitreally injected ASL exosomes were predominantly delivered to the area of CNV including ONL, RPE, and choroid in laser-induced CNV mouse models with 89.5% of colocalization with integrin αv. Part of exosomes was also taken intracellularly to vascular endothelial cells and macrophages. After intravitreal injection, neither naive exosomes nor ASL exosomes induced immediate reactive gliosis. Conclusions: Intravitreally delivered retinal multicell-derived exosomes have good retinal penetration, and ASL modification of exosomes actively targets CNV with no immediate reactive gliosis. ASL exosomes have a great potential to serve as an intraocular drug delivery vehicle, allowing an active targeting strategy.

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v at the site of CNV.…”

Section: Discussionmentioning

confidence: 99%

Intraocular RGD-Engineered Exosomes and Active Targeting of Choroidal Neovascularization (CNV)

Pollalis

Kim

Nair

et al. 2022

Cells

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“…Саме тому було припущено, що anti-VEGF терапія значно покращить зір і якість життя пацієнтів із "вологою" фор-мою ВМД. Однак, приблизно одна третина пацієнтів не отримує ефекту від даної терапії через макулярний фіброз або атрофію тощо [13,17,18].…”

Section: вступunclassified

The influence of the rs2010963 polymorphism of the VEGFA gene on the response to the treatment of the “wet” form of age-related macular degeneration

Малачкова¹,

Al-Jarrah²

2022

Rep. of Vinnytsia Nation. Med. Univ.

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Annotation. Age-related macular degeneration is one of the main causes of vision loss in the elderly. By 2040, the population with age-related macular degeneration (AMD) is expected to reach about 288 million. It was hypothesized that anti-VEGF therapy would significantly improve the vision and quality of life of patients with “wet” AMD. However, approximately one-third of patients do not benefit from this therapy, including due to macular fibrosis or retinal atrophy. It is believed that the role of genetic predisposition may also influence treatment resistance. Therefore, the aim of the study was to identify the response to treatment with aflibercept in patients with “wet” AMD with polymorphism variants rs2010963 of the VEGFA gene. The research group included 162 people who had a confirmed “wet” form of AMD, in contrast to which 105 people were included in the comparison group. The “wet” form of AMD was detected with the help of optical coherence tomography using the ILM-RPE parameter, while the patients received monthly intravitreal injections of the AVGF drug aflibercept (50 μl of solution – the recommended dose). Real-time polymerase chain reaction was used to determine the rs2010963 polymorphism of the VEGFA gene. Statistical processing of the obtained results was carried out using Statistica 10.0 and SPSS 23.0 programs. It was established that the presence of the mutant C allele increases the risk of resistance to anti-VEGF therapy both after the first injection and after the full course of treatment (p<0.05). A strong influence of the polymorphism after the therapy was observed in the areas of OCT 2, which corresponds to the inner upper part of the retina (OR=5.89; 95% CI 3.31 – 10.49) and OCT 3, which corresponds to the central area of the retina (OR=4, 76; 95% CI 2.79 – 8.13). At the same time, there is an influence of mutant genotypes on treatment: yes, carrying both the heterozygous variant of ONP and the homozygous variant for the minor allele significantly contributed to the emergence of resistance to treatment (p<0.05). A pronounced degree of association of rs2010963 of the VEGFA gene with the emergence of resistance to the action of anti-VEGF drugs was revealed. Thus, the heterogeneity of RR and 95% CI indicators in different areas of the retina likely indicates a “zone-dependent” effect of rs2010963 of the VEGFA gene on the retina, which may be related to the peculiarities of its functioning and pathogenetic effect on the organ of vision.

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“…Targeted intraceptor nanoparticle therapy is administered intravenously and can cross the blood-retinal barrier, which is generally a major obstacle for intravenous delivery. Furthermore, this therapy is nontoxic in vivo, suggesting that this could provide a means for alternative drug delivery route to treat nAMD [60,61].…”

Section: New Therapies For Namd—thinking Beyond Anti-vegfsmentioning

confidence: 99%

New Therapies of Neovascular AMD—Beyond Anti-VEGFs

Yerramothu

2018

Vision

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Neovascular age-related macular degeneration (nAMD) is one of the leading causes of blindness among the aging population. The current treatment options for nAMD include intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). However, standardized frequent administration of anti-VEGF injections only improves vision in approximately 30–40% of nAMD patients. Current therapies targeting nAMD pose a significant risk of retinal fibrosis and geographic atrophy (GA) development in nAMD patients. A need exists to develop new therapies to treat nAMD with effective and long-term anti-angiogenic effects. Recent research on nAMD has identified novel therapeutic targets and angiogenic signaling mechanisms involved in its pathogenesis. For example, tissue factor, human intravenous immune globulin, interferon-β signaling, cyclooxygenase-2 (COX-2) and cytochrome P450 monooxygenase lipid metabolites have been identified as key players in the development of angiogenesis in AMD disease models. Furthermore, novel therapies such as NACHT, LRR and PYD domains containing protein 3 (NLRP3) inflammasome inhibition, inhibitors of integrins and tissue factor are currently being tested at the level of clinical trials to treat nAMD. The aim of this review is to discuss the scope for alternative therapies proposed as anti-VEGFs for the treatment of nAMD.

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Targeted Intraceptor Nanoparticle for Neovascular Macular Degeneration: Preclinical Dose Optimization and Toxicology Assessment

Cited by 19 publications

References 34 publications

Intraocular RGD-Engineered Exosomes and Active Targeting of Choroidal Neovascularization (CNV)

Intraocular RGD-Engineered Exosomes and Active Targeting of Choroidal Neovascularization (CNV)

The influence of the rs2010963 polymorphism of the VEGFA gene on the response to the treatment of the “wet” form of age-related macular degeneration

New Therapies of Neovascular AMD—Beyond Anti-VEGFs

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