Hyaluronic acid-based nanoparticles to deliver drugs to the ocular posterior segment

Figures & data

Figure 1. Chemical structure of HA.

Figure 2. The structure of the eyeball. A: The ocular posterior segment located behind the lens, containing the vitreous body, the retina, the optic disc, the choroid and most of the sclera. The lens and the part in front of it, called the anterior segment. B: Two elimination routes after intravitreal administration. The anterior clearance route refers to the path excluded via trabecular meshwork outflow channels (yellow arrows), while the posterior route is the exit through the iris, ciliary body and retina (black arrows). C: Schematic diagrams of the retina.

Figure 3. The advantages of HA modification in nanomaterials.

Figure 4. The schematic of nanoparticles.

Table 1. Advantages and drawbacks of nanoparticles for intravitreal administration.

Nanoparticles	Advantages	Drawbacks	Ref
Lipid nanoparticles	Low or absence of in-vivo toxicity	Drug expulsion during storage (for SLN)	(Khosa et al., 2018; Costa et al., 2021; Navarro-Partida et al., 2021)
	Economic and solvent-free production techniques	Restricted loading capacity of hydrophilic drug (for SLN and NLC)
	Accessibility
	Possibility to be autoclaved or sterilized
	Great kinetic stability compared to liposomes and niosomes
	Condensing and protecting the genetic material
Liposomes	Biocompatibility	Visual blurring	(Bochot & Fattal, 2012; Akbarzadeh et al., 2013; Chaurasiya et al., 2022; Taléns-Visconti et al., 2022)
	Enhancing the stability of entrapped drugs	Inflammation caused by cationic surface charge
	Increasing the drug half-life in the vitreous	Possibility of aggregation during storage or in vivo when colloidal stability is poor
	Reducing the drug toxicity	High-cost of production
	Possibility of ligands attachment
Micelles	Enhancing the solubility and therapeutic efficacy of highly hydrophobic drugs	Ocular irritation	(Wu et al., 2016; Gote et al., 2020; Rodríguez-Acosta et al., 2021)
	Enhancing the stability of entrapped drugs	Limitation to large-scale production
	Accessibility and low-cost of production
	Enabling controlled drug release kinetics
	Ease of surface modification
Dendrimers	Intrinsic ability of the PAMAM dendrimers to target neuroinflammation-related cells	Cytotoxicity caused by cationic surface charge	(Khosa et al., 2018; Sathe and Bharatam, 2022)
	A well-defined shape, size, and narrow polydispersity
Human serum albumin	High drug loading capacity	Unstable	(Koo et al., 2012; Piazzini et al., 2019; Gao et al., 2020)
	Nonimmunogenicity
	Penetrating ILM by interaction with Müller cells
Gold nanoparticles	Biocompatibility	Need ligands to stabilize	(Kim et al., 2011; Masse et al., 2019; Bharadwaj et al., 2021)
	Accessibility
	Endowing precisely control over size and shape
	Antiangiogenic and anti-inflammatory
Niosomes	Biodegradability	Lower drug loading capacity compared to liposomes	(Hong et al., 2009; Gan et al., 2013; Yasamineh et al., 2022)
	Biocompatibility
	Nonimmunogenicity
	Chemically stable
	Encapsulation of both hydrophilic and hydrophobic drug molecule

Note: SLN, solid lipid nanoparticles; NLC, nanostructured lipid carriers; PAMAM, polyamidoamine; ILM, inner limited membrane.

Table 2. HA-based nanoparticles.

Nanocarriers	Drug	MW of HA	Size	Zeta potential	Type of HA coating	Disorder	Benefits of HA modification	Ref
Lipid nanoparticles	NA	10–100 kDa; 200–400 kDa	320 nm	‒25 mV	Electrostatic adsorption	Uveitis	Slowing down elimination in the retina and RPE/choroid, targeting to CD44-positive RPE cells	(Gan et al., 2013)
Solid lipid nanoparticles/protamine	Plasmid (pCMS–EGFP)	150 kDa; 500 kDa; 1,630 kDa	240–340 nm	+30 mV–+40 mV	Electrostatic adsorption	X-linked juvenile retinoschisis	Improving the cellular uptake and transfection, facilitating the release of DNA.	(Apaolaza et al., 2014)
Solid lipid nanoparticles/protamine	Plasmid (pCAG-GFP_CMV_RS1)	150 kDa	235 ± 28 nm	+31.4 ± 0.8 mV	Electrostatic adsorption	X-linked juvenile retinoschisis	Doing favor on the loosening of the plasmid in cytoplasmic, accelerating the diffusion process in the vitreous	(Apaolaza et al., 2015)
N,N′-cystaminebisacrylamide-4-aminobutanol (p(CBA-ABOL))/pDNA complexes	Plasmid (pGL4.13 and gwiz-GFP)	22 kDa;137 kDa; 2,700 kDa	647 ± 19 nm; 343 ± 4 nm; NA	‒22 ± 1 mV; −29.9 ± 0.5 mV; –37 ± 2 mV	Electrostatic adsorption	Retina dystrophies with a genetic cause	Stabilizing the nanoparticles with negative charges, improving the mobility in vitreous, increasing the cellular uptake via CD44	(Martens et al., 2015)
Solid lipid nanoparticles/protamine	Plasmid (pCMV-GFP_mOPS-RS1)	150 kDa	223 ± 20 nm	+31.5 ± 1.1 mV	Electrostatic adsorption	X-linked juvenile retinoschisis	Favor of the mobility of nano polymers through the vitreous and retina, facilitating the cellular uptake via CD44, improving the transfection via plasmid loosening	(Apaolaza et al., 2016)
Human serum albumin	Connexin43 mimetic peptide	120 kDa	252.70 ± 7.29 nm	‒43.97 ± 0.38 mV	Electrostatic adsorption	Retinal ischemia and inflammatory disorders	Enhancing the cellular uptake and retinal penetration via CD44, stabilizing the nanoparticles and alleviating the cytotoxicity, presenting more sustained and constant drug release	(Huang et al., 2017, 2018)
PolysiRNA polyplex	PolysiRNA targeting mouse VEGF-A	5 kDa	260.7 ± 43.27 nm	‒4.98 ± 0.47 mV	Electrostatic adsorption	Age-related macular degeneration	Overcoming the retinal barriers and cellular uptake by RPE cells via CD44 receptors	(Lee et al., 2016)
DOTAP/DOPE liposomes	Plasmid (pGL4.13 and gwiz-GFP)	1,600 kDa	159 ± 1 nm; 204 ± 4 nm	‒36 ± 1; −20 ± 4 mV	Electrostatic adsorption;Covalent adsorption	NA	Improving the mobility in vitreous, covalent adsorption of HA significantly promoting the transgene expression than by electrostatic adsorption	(Martens et al., 2017)
DOTAP/DOPE niosomes	Plasmid (pEGFP-C1)	1,900–3,900 kDa	286.20 ± 2.19 nm	‒41.1 ± 1.16 mV	Covalent adsorption	Genetic or acquired retina diseases	Targeting retina cells through interaction between HA and CD44, achieving remarkable transfection efficiency	(Qin et al., 2018)
TransIT-mRNA comlexes	mRNA (pEGFFP)	20 kDa; 200 kDa;>1,800 kDa	125–1,000 nm	‒40mV to +10 mV	Electrostatic adsorption	NA	Increasing the mobility in vitreous	(Devoldere et al., 2019)
Gold nanoparticles	NA	5 kDa	53.22 ± 3.36 nm; 90.01 ± 2.58 nm	‒24.73 ± 1.47 mV; ‒22.23 ± 1.77 mV	Covalent adsorption	Intraocular vascular disorders	Stabilizing the particles, enhancing the diffusion ability in vitreous, targeting to the deep retina tissues	(Apaolaza et al., 2020)
Light-activated liposomes	Indocyanine green	8–15 kDa	104 ± 25 nm; 68 ± 16nm	‒11.27 ± 0.21 mV; NA	Covalent adsorption	NA	Improving the stability and mobility in vitreous and plasma	(Kari et al., 2020)
Dendrimer PRHF/NLS/DNA complex; liposome	Plasmid (Flt23K)	10 kDa	200–650 nm	‒20 mV to +15 mV	Covalent adsorption	Age-related macular degeneration	Leading to higher cellular uptake due to the binding to CD44, improving the stability and mobility in vitreous, enhancing the penetration in retina tissues	(Tan et al., 2021)

Note: MW, molecular weight; HA, hyaluronic acid or hyaluronan; CD44, cluster-determined 44; RPE, retina pigment epithelium; GFP, green fluorescent protein; VEGF, vascular endothelial growth factor; DOTAP, 1,2-dioleoyl-3-trimethylammonium-propane; DOPE, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; mRNA, messenger RNA; NLS, nuclear localization signal; NA, not accessible.

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