Nanoparticle to target cancer
Inventors
Smith, Jill P. • Stern, Stephan • Mahmud, Abdullah
Assignees
Georgetown University • US Department of Health and Human Services
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Publication Number
US-11246881-B2
Publication Date
2022-02-15
Expiration Date
2037-03-15
Abstract
A construct, or a pharmaceutically acceptable salt thereof, comprising: (a) a polyethylene glycol-block-poly(L-lysine) polymer moiety, wherein the polyethylene glycol is thiol-functionalized;(b) a cholecystokinin-B (CCK-B) receptor ligand coupled to the polyethylene glycol of the polymer moiety; and(c) a siRNA complexed with the poly(L-lysine) of the polymer moiety,wherein the construct is neutralized.
Core Innovation
The invention discloses a construct, or a pharmaceutically acceptable salt thereof, comprising a polyethylene glycol-block-poly(L-lysine) polymer moiety with thiol-functionalized polyethylene glycol, a cholecystokinin-B (CCK-B) receptor ligand coupled to the polyethylene glycol, and a siRNA complexed with the poly(L-lysine) of the polymer moiety, wherein the construct is neutralized. The polymer moiety and ligand form a nanoparticle designed to selectively target the CCK-B receptor, which is overexpressed on pancreatic cancer cells, and deliver siRNA to inhibit pancreatic cancer growth and metastases.
The construct addresses the problem that pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with limited effective treatments because most agents are not tumor-selective and RNA interference therapeutics break down in the bloodstream without effective delivery. The invention solves the need for a nontoxic and tumor-specific gene delivery system enabling RNAi therapy to inhibit critical driver genes such as GASTRIN and mutated KRAS in pancreatic cancer by using a targeted polyethylene glycol-block-poly(L-lysine) nanoparticle that protects siRNA and delivers it specifically to the cancer cells via the CCK-B receptor.
This targeted nanotechnology approach includes a stable thioether linkage to conjugate the targeting ligand (e.g., gastrin-10 peptide) to the polymer, forming polyplex micelle nanoparticles with siRNA in the core and PEG with ligand on the surface. These nanoparticles demonstrate selective binding and uptake in pancreatic tumors, inhibit gastrin expression, reduce tumor growth, and prevent metastases in murine models of pancreatic cancer. The invention also discloses methods to produce and use such constructs and pharmaceutical compositions for treating cancers expressing the CCK-B receptor.
Claims Coverage
The patent includes multiple independent claims covering the composition of the construct, its pharmaceutical compositions, methods of making the construct, and methods of treating cancer, with inventive features centered on the specific polymer-ligand-siRNA complex and its properties.
Targeted polymer-siRNA nanoparticle composition
A construct comprising a thiol-functionalized polyethylene glycol-block-poly(L-lysine) polymer moiety, a cholecystokinin-B (CCK-B) receptor ligand coupled to the polyethylene glycol, and siRNA complexed with the poly(L-lysine), wherein the construct is neutralized and forms a nanoparticle with an average hydrodynamic size below 100 nm.
Use of CCK-B receptor ligands for targeting
The coupling of specific CCK-B receptor ligands, such as gastrin-10 peptide or a DNA aptamer, to the polyethylene glycol block through maleimide-thiol chemistry, conferring target specificity to the nanoparticle for cancer cells overexpressing the CCK-B receptor.
Electrostatic complexation of siRNA with polymer
Complexing siRNA targeting genes like GASTRIN and mutant KRAS electrostatically with the poly(L-lysine) block of the polymer to form stable polyplex micelle nanoparticles with siRNA in the core protected from degradation.
Pharmaceutical compositions comprising the constructs
Formulations containing the described constructs with pharmaceutically acceptable carriers suitable for various administration routes including parenteral, sublingual, intranasal, topical, and others.
Methods of treatment using targeted siRNA constructs
Administering therapeutically effective amounts of the described CCK-B receptor ligand-targeted polymer-siRNA constructs to treat cancers that express CCK-B receptors, especially pancreatic ductal adenocarcinoma, resulting in inhibition of tumor growth and metastasis.
The independent claims focus on the novel thiol-functionalized PEG-PLL polymer conjugated with a CCK-B receptor ligand and complexed with siRNA to form neutralized nanopolyplexes that specifically target and deliver siRNA to CCK-B receptor-expressing cancers, particularly pancreatic cancer, along with their pharmaceutical formulations, preparation methods, and therapeutic use.
Stated Advantages
Selective delivery of siRNA to pancreatic cancer cells overexpressing the CCK-B receptor, enhancing tumor targeting and uptake while minimizing off-target effects.
Protection of siRNA from degradation in the bloodstream by complexation within the nanoparticle core, ensuring effective gene silencing.
Demonstrated inhibition of pancreatic cancer growth and metastases in vitro and in vivo using targeted gastrin siRNA nanoparticles.
Biodegradable and nontoxic nanoparticle design minimizing toxicity compared to other delivery vehicles.
Versatility to complex other therapeutically active agents beyond siRNA, allowing treatment of various cancer-related targets.
Documented Applications
Treatment of pancreatic ductal adenocarcinoma by administering the targeted siRNA nanoparticle to inhibit tumor growth and prevent metastasis.
Therapy for other cancer types expressing the CCK-B receptor including colorectal cancer, gastric cancer, distal esophageal adenocarcinoma, medullary thyroid cancer, small cell lung cancer, and carcinoid tumors.
Delivery of RNAi-based gene therapy targeting driver genes such as GASTRIN and mutated KRAS in pancreatic cancer.
Use of the nanoparticle platform to deliver various RNA-based therapeutics including microRNAs, antisense oligonucleotides, aptamers, and synthetic mRNAs for cancer treatment.
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