Retinal Delivery of the Protein Kinase C-β Inhibitor Ruboxistaurin Using Non-Invasive Nanoparticles of Polyamidoamine Dendrimers

Abstract

Ruboxistaurin (RBX) is an anti-vascular endothelial growth factor (anti-VEGF) agent that is used in the treatment of diabetic retinopathy and is mainly given intravitreally. To provide a safe and effective method for RBX administration, this study was designed to develop RBX nanoparticles using polyamidoamine (PAMAM) dendrimer generation 5 for the treatment of diabetic retinopathy. Drug loading efficiency, and in vitro release of proposed complexes of RBX: PAMAM dendrimers were determined and the complexation ratio that showed the highest possible loading efficiency was selected. The drug loading efficiency (%) of 1:1, 2.5:1, and 5:1 complexes was 89.2%, 96.4%, and 97.6%, respectively. Loading capacities of 1:1, 2.5:1, and 5:1 complexes were 1.6%, 4.0%, and 7.2% respectively. In comparison, the 5:1 complex showed the best results in the aforementioned measurements. The in vitro release studies showed that in 8 h, the RBX release from 1:1, 2.5:1, and 5:1 complexes was 37.5%, 35.9%, and 77.0%, respectively. In particular, 5:1 complex showed the highest drug release. In addition, particle size measurements showed that the diameter of empty PAMAM dendrimers was 214.9 ± 8.5 nm, whereas the diameters of loaded PAMAM dendrimers in 1:1, 2.5:1, 5:1 complexes were found to be 461.0 ± 6.4, 482.4 ± 12.5, and 420.0 ± 7.1 nm, respectively. Polydispersity index (PDI) showed that there were no significant changes in the PDI between the free and loaded PAMAM dendrimers. The zeta potential measurements showed that the free and loaded nanoparticles possessed neutral charges due to the presence of anionic and cationic terminal structures. Furthermore, the safety of this formulation was apparent on the viability of the MIO-M1 cell lines. This nanoformulation will improve the therapeutic outcomes of anti-VEGF therapy and the bioavailability of RBX to prevent vision loss in patients with diabetic retinopathy.

Role of Nanotechnology in Overcoming the Multidrug Resistance in Cancer Therapy: A Review

“…Nanotechnology has been used in medicine more and more over the past few decades, including applications for safer and more efficient tumor targeting, detection, and treatment [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Drug delivery methods based on nanoparticles (NPs) have demonstrated a number of benefits in the treatment of cancer, including good pharmacokinetics, accurate targeting of tumor cells, a decrease in adverse effects, and reduced drug resistance [ 21 , 22 , 23 , 24 , 25 ]. Nevertheless, nanomedicine-based formulations have some demerits, such as difficulty in physical handling due to smaller size, particle aggregation, limited drug loading, and burst release [ 19 , 20 ].…”

Smart Nanocarriers for the Treatment of Retinal Diseases

“…Therefore, polymeric carriers are employed for delivering drugs to treat retinal diseases, such as acyclovir, superoxide dismutase, and imatinib. 11,12,95,96 PLGA, PEG, and other similar compounds have been frequently utilized as carriers for delivering drugs in the field of ophthalmic medicine. Through clinical trials, they have demonstrated the ability to sustain the release of drugs while maintaining an acceptable safety profile.…”

“…This renders them suitable for utilization in intricate physiological environments, including the posterior of the eye. , The diverse nature of polymer molecules, along with their varying hydrophobicity, renders them highly inclusive of both hydrophilic and hydrophobic drugs as well as biologically active proteins. Therefore, polymeric carriers are employed for delivering drugs to treat retinal diseases, such as acyclovir, superoxide dismutase, and imatinib. ,,, PLGA, PEG, and other similar compounds have been frequently utilized as carriers for delivering drugs in the field of ophthalmic medicine. Through clinical trials, they have demonstrated the ability to sustain the release of drugs while maintaining an acceptable safety profile. , Furthermore, noninvasive topical delivery polymer drug delivery systems are extensively employed in the treatment of retinal diseases. ,,− …”

“…Nanocarriers, including AAV carriers, liposomes, micelles, dendrimers, and hydrogels have undergone extensive scrutiny for drug delivery to the retina. − To reach the posterior eye, nanocarriers must overcome several obstacles, both static and dynamic. Static barriers encompass the different layers of ocular tissues such as the cornea, conjunctiva, and sclera as well as the vascular blood–retinal and blood–aqueous barriers.…”

Applications of nanomaterials in anti‐VEGF treatment for ophthalmic diseases

“…For the treatment of DR, it is a safe alternative to invasive intravitreal injection. The study conducted by Rehab A. et al employed polyamidoamine (PAMAM) dendrimer nanoparticles and designed a non‐invasive therapeutic approach using Ruboxistaurin (RBX) in order to optimize the treatment outcomes for diabetic retinopathy 97 . Additionally, Xin et al demonstrated that treatment with G4PAMAM/VEGF Antisense oligodeoxynucleotides (VEGFASODN) effectively hinders the proliferation of retinoblastoma (SO‐RB50) cells.…”