Method of delivering genes and drugs to a posterior segment of an eye
Inventors
Mohapatra, Shyam S. • Mohapatra, Subhra • Markoutsa, Eleni
Assignees
US Department of Veterans Affairs • University of South Florida St Petersburg
Publication Number
US-11752220-B2
Publication Date
2023-09-12
Expiration Date
2039-08-05
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Abstract
A multifunctional dendrimer nanoparticle and method of treating diseases of the posterior segment of the eye is presented. The functionalized polyamidoamine (PAMAM) dendrimer effectively delivers drugs and/or genes to the posterior eye, thereby providing for the effective, non-invasive, and topical treatment of diseased in the posterior eye. The multifunctional dendrimer nanoparticle has shRNA-encoding DNA and small molecule drug encapsulated cyclodextrin complexed to the outer surface of the dendrimer for delivery to the posterior segment of the eye.
Core Innovation
The invention relates to a multifunctional dendrimer nanoparticle and a method of treating diseases of the posterior segment of the eye. The functionalized polyamidoamine (PAMAM) dendrimer effectively delivers drugs and/or genes to the posterior eye, enabling effective, non-invasive, and topical treatment. The multifunctional dendrimer nanoparticle incorporates shRNA-encoding DNA and a small molecule drug encapsulated in cyclodextrin complexed on the outer surface of the dendrimer for delivery to the posterior segment.
The problem addressed is that the topical administration of therapeutics to the posterior segment of the eye is largely ineffective due to multiple anatomical and physiological barriers such as the corneal and conjunctival epithelium, blood aqueous barriers, and blood retinal barriers. These barriers limit drug penetration, resulting in low bioavailability (<5%) and necessitating invasive intravitreal injections, which are expensive and difficult to repeat. Existing nanoparticle-based methods have limitations in targeting, efficacy, and safety, including off-target effects.
The invention provides a nanoformulation and a non-invasive topical method of delivery that leads to drug availability in the posterior eye. Specifically, it presents a multifunctional dendrimer nanoparticle platform where PAMAM dendrimers are surface functionalized to target delivery of short hairpin RNAs (shRNAs) and small molecules to the retina. The dendrimers are complexed with small molecule drugs encapsulated in cyclodextrin to improve solubility, and the surfaces may be further functionalized with targeting agents such as hyaluronic acid, cholera toxin B domain, RGD peptide, or Tat peptide to target retina-specific receptors like CD44. This approach overcomes prior art shortcomings by allowing for non-invasive, topical, effective delivery to the posterior eye.
Claims Coverage
The independent claim covers a method involving a composition comprising multifunctional dendrimer nanoparticles for topical delivery to the posterior segment of the eye. The main inventive features include the structure of the dendrimer nanoparticle, its functionalization with genetic and drug components, targeting agents, and the non-invasive administration method.
Modified polyamidoamine dendrimer nanoparticle with controlled size
A PAMAM dendrimer nanoparticle is modified using molecular extrusion to remove large particles and aggregates to achieve a uniform size of about 10 nm, improving delivery effectiveness and stability.
Complexation of short hairpin RNA-encoding DNA molecule on dendrimer surface
At least one shRNA-encoding DNA molecule is complexed to the outer surface of the modified PAMAM dendrimer nanoparticle, enabling gene delivery to the posterior segment of the eye.
Conjugation of natural cyclodextrin encapsulating pioglitazone on dendrimer surface
Natural cyclodextrin encapsulating the small molecule drug pioglitazone is conjugated to the outer surface of the dendrimer nanoparticle to enhance solubility and bioavailability of the drug.
Inclusion of targeting agents specific to the CD44 receptor
A targeting agent selected from hyaluronic acid, cholera toxin B domain, RGD peptide, or Tat peptide is conjugated to the dendrimer's surface to specifically target CD44 receptors in the posterior eye.
Topical administration method targeting the posterior segment
The composition containing the multifunctional dendrimer nanoparticles is topically administered as eye drops to the patient, enabling non-invasive delivery to the posterior segment of the eye.
The claims cover a multifunctional dendrimer nanoparticle system including modified PAMAM dendrimers complexed with shRNA DNA, natural cyclodextrin-encapsulated drugs, and targeting agents, formulated in a pharmaceutically acceptable carrier. The method administers this composition topically to achieve targeted delivery to the posterior segment of the eye non-invasively.
Stated Advantages
Provides a topical, non-invasive, and effective drug and gene delivery method to the posterior segment of the eye, avoiding invasive procedures.
Enhances solubility and bioavailability of poorly soluble small molecule drugs via cyclodextrin encapsulation.
Targets retinal cells specifically through surface functionalization with targeting agents such as hyaluronic acid, improving selectivity and accumulation.
Improves stability and colloidal properties through PEGylation and surface modifications.
Enables gene delivery with high transfection efficiency due to dendrimer properties, including endosomal escape facilitated by the proton sponge effect.
Documented Applications
Treatment of posterior segment eye diseases including glaucoma, age-related macular degeneration (ARMD), diabetic retinopathy (DR), cytomegalovirus (CMV) retinitis, proliferative vitreoretinopathy, Stargardt disease, retinoblastoma, and uveitis via topical administration.
Delivery of shRNA-encoding DNA and small molecule drugs such as pioglitazone to the retina and posterior segment of the eye.
Use as an alternative to invasive intravitreal injections for ocular diseases requiring gene and drug therapy.
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