Method of delivering genes and drugs to a posterior segment of an eye
Inventors
Mohapatra, Shyam S. • Mohapatra, Subhra • Markousta, Eleni
Assignees
US Department of Veterans Affairs • University of South Florida St Petersburg
Publication Number
US-11110183-B2
Publication Date
2021-09-07
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 presents a multifunctional dendrimer nanoparticle and a method for treating diseases of the posterior segment of the eye using this nanoparticle. The functionalized polyamidoamine (PAMAM) dendrimer effectively delivers drugs and/or genes to the posterior eye, enabling an effective, non-invasive, and topical treatment for diseases affecting this area. The dendrimer nanoparticle incorporates shRNA-encoding DNA and a small molecule drug encapsulated cyclodextrin complexed to the dendrimer's outer surface for delivery to the posterior segment.
The background identifies the problem of delivering therapeutics effectively to the posterior segment of the eye. Topical administration methods like eye drops have limited effectiveness due to poor drug solubility and an inability to pass physical ocular barriers such as the corneal and conjunctival epithelium, blood aqueous barriers, and blood retinal barriers. Current treatments require invasive intravitreal injections, which are expensive, difficult to repeat, and potentially unsafe.
The innovation addresses these limitations by developing a topical multifunctional dendrimer nanoparticle (tMDN) platform. This platform uses surface-functionalized PAMAM dendrimers complexed with short hairpin RNA (shRNA)-encoding DNA and small molecule drugs encapsulated in cyclodextrin, allowing non-invasive topical delivery specifically targeting the retina. The dendrimer's properties facilitate gene and drug delivery past ocular barriers to the posterior eye, potentially offering a safer and more effective alternative to invasive methods.
Claims Coverage
There is one independent claim describing a drug delivery system composed of specific multifunctional dendrimer nanoparticles and their components. This claim details the composition and key functional features of the system.
Multifunctional dendrimer nanoparticle size optimization
The nanoparticle utilizes a modified PAMAM dendrimer processed through molecular extrusion to remove large particles and aggregates, achieving a uniform size of about 10 nm.
Complexation of gene and drug components to the dendrimer surface
The outer surface of the dendrimer is complexed with at least one short hairpin RNA (shRNA)-encoding DNA molecule and with natural cyclodextrin encapsulating pioglitazone, enabling combined gene and drug delivery.
Targeting agent conjugation for receptor specificity
The dendrimer surface is conjugated with a targeting agent that specifically binds to the CD44 receptor, selected from hyaluronic acid, cholera toxin B domain, arginylglycylaspartic acid (RGD) peptide, and Tat peptide, to enhance targeting of the posterior eye.
Inclusion of a pharmaceutically acceptable carrier
The system includes a pharmaceutically acceptable carrier suitable for ocular topical administration of the multifunctional dendrimer nanoparticles.
The independent claim covers a multi-component nanoparticle drug delivery system comprising size-optimized PAMAM dendrimers functionalized with shRNA encoding DNA, cyclodextrin-encapsulated pioglitazone, and targeting agents that bind CD44 receptors, provided in a suitable pharmaceutical carrier for topical delivery to the posterior segment of the eye.
Stated Advantages
Enables effective delivery of drugs and genes to the posterior segment of the eye via a topical, non-invasive method.
Avoids the need for invasive, expensive, and difficult-to-repeat procedures like intravitreal injections.
Enhanced bioavailability and stability of poorly soluble small molecule drugs through encapsulation in cyclodextrins.
Targeting agents on the nanoparticle surface increase specificity and accumulation in retinal tissues.
PEG conjugation improves colloidal stability and protects DNA complexes on the nanoparticle surface.
Documented Applications
Topical treatment of diseases of the posterior segment of the eye including retinal disorders.
Non-invasive delivery of therapeutic agents such as shRNA plasmids and small molecule drugs like pioglitazone to the eye's retina.
Potential use in treating age-related macular degeneration, diabetic retinopathy, glaucoma, and other posterior eye diseases.
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