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Porous nanoparticle-supported lipid bilayers (protocells) for targeted delivery including transdermal delivery of cargo and methods thereof

A protocell, cell-targeting technology, applied in other methods of inserting foreign genetic material, liposome delivery, antibody mimics/scaffolds, etc., can solve problems such as difficult to control release

Inactive Publication Date: 2014-09-03
STC UNM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Third, release of cargo from liposomes is instantaneous upon liposome rupture, making controlled release difficult

Method used

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  • Porous nanoparticle-supported lipid bilayers (protocells) for targeted delivery including transdermal delivery of cargo and methods thereof
  • Porous nanoparticle-supported lipid bilayers (protocells) for targeted delivery including transdermal delivery of cargo and methods thereof
  • Porous nanoparticle-supported lipid bilayers (protocells) for targeted delivery including transdermal delivery of cargo and methods thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0264] Ligands target protocells

[0265]As provided in the following examples, porous nanoparticle-supported lipid bilayers (protocells) formed via the fusion of liposomes and nanoporous silica particles are a new type of nanocarrier that addresses issues related to cancer therapy and There are multiple challenges associated with the targeted delivery of diagnostics. Like liposomes, protocells are biocompatible, biodegradable, and non-immunogenic, but their nanoporous silica core confers a greatly increased High load capacity and extended double layer stability. Furthermore, the porosity and surface chemistry of the core can be tuned to facilitate encapsulation of various therapeutic agents such as drugs, nucleic acids and protein toxins. The release rate of the cargo can be controlled by the pore size and the overall degree of compression of the silica, allowing protocells to be used in applications requiring burst release or controlled release characteristics. Finally, t...

Embodiment 2

[0394] Transdermal delivery of imatinib

[0395] The epidermis is the uppermost layer of the skin and can be further divided into 4 layers. The outermost layer of the epidermis is the stratum corneum, approximately 10-20 pm thick; this is the main challenge associated with transdermal delivery. The other 3 layers of the epidermis can collectively be classified as viable epidermis; this viable epidermis is 50-100pm thick. The viable epidermis contains immune cells (Langerhan cells), epithelial keratinocytes, sensory nerves (Megger cells), and a network of capillary beds, venules, and arterioles. The dermis is 1-2 mm thick and is composed of alveoli containing other types of immune cells (mast cells, lymphocytes, macrophages, neutrophils, plasma cells), fibroblasts, and various fibers (nerve fibers, collagen, elastic fibers). Furthermore, 1a explains the 4 main methods by which cargo delivery across the stratum corneum can be taken. (a) Intercellular pathway, (b) Follicular ...

Embodiment 3

[0426] siRNA-loaded, SP94-targeted protocell-induced apoptosis

[0427] result

[0428] Characterization of siRNA-loaded protocells. Silica nanoparticles as in Carroll et al. 35 The preparation, and has >600m 2 BET surface area per gram, ~65% pore volume fraction, and multimodal pore morphology consisting of large (20-30 nm), surface-accessible pores interconnected by 6-12 nm pores (see figure 2 BX3-CX3). Silica nanoparticles were separated by size prior to loading with siRNA (or ricin A chain) as described in the Methods section (see Figure 2A X3). image 3 AX3 shows the siRNA loading capacity of protocells or lipoplexes constructed using a range of strategies. Lipid complexes composed of zwitterionic phospholipids and DOPC per 10 10 Particles encapsulate ~10 nM siRNA. Construction of lipoplexes composed of the cationic lipid, DOTAP, resulted in a 5-fold increase in siRNA loading, presumably due to attractive electrostatic interactions between negatively charged nuc...

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Abstract

The present invention is directed to protocells for specific targeting of hepatocellular and other cancer cells which comprise a nanoporous silica core with a supported lipid bilayer; at least one agent which facilitates cancer cell death (such as a traditional small molecule, a macromolecular cargo (e.g. siRNA or a protein toxin such as ricin toxin A-chain or diphtheria toxin A-chain) and / or a histone-packaged plasmid DNA disposed within the nanoporous silica core (preferably supercoiled in order to more efficiently package the DNA into protocells) which is optionally modified with a nuclear localization sequence to assist in localizing protocells within the nucleus of the cancer cell and the ability to express peptides involved in therapy (apoptosis / cell death) of the cancer cell or as a reporter, a targeting peptide which targets cancer cells in tissue to be treated such that binding of the protocell to the targeted cells is specific and enhanced and a fusogenic peptide that promotes endosomal escape of protocells and encapsulated DNA. Protocells according to the present invention may be used to treat cancer, especially including hepatocellular (liver) cancer using novel binding peptides (c-MET peptides) which selectively bind to hepatocellular tissue or to function in diagnosis of cancer, including cancer treatment and drug discovery.

Description

[0001] Related applications and government support [0002] This application claims U.S. Provisional Application 61 / 547,402, entitled "Engineering Nanoporous Particle-Supported Lipid Bilayers ('Protocells') for Transdermal Cargo Delivery," filed October 14, 2011; filed December 21, 2011 Priority to US Provisional Application 61 / 578,463, entitled "Engineering Nanoporous Particle-Supported Lipid Bilayers ('Protocells') for Transdermal Cargo Delivery," the entire contents of which are hereby incorporated by reference. [0003] This application also claims priority to US Provisional Application 61 / 577,410, filed December 19, 2011, entitled "Delivery of Therapeutic Macromolecular Cargos by Targeted Protocells," the entire contents of which are hereby incorporated by reference. [0004] This invention was made with government support under National Institutes of Health Grant No. PHS 2 PN2EY016570B, National Cancer Institute Grant No. 1U01CA151792-01, Air Force Scientific Research Offi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/16A61K47/48A61K49/08A61K48/00A61K38/17A61K31/7105A61K31/7088A61K33/24A61K33/242A61K33/243
CPCA61K31/713A61K9/0014A61K49/0082A61K9/1271A61K31/7088A61K31/7105C12N15/88A61K49/0423C12N2810/40C07K7/06C07K2319/00A61K9/107A61K45/06A61K38/00A61K9/5078B82Y5/00A61K47/48861A61K31/192A61K31/465A61K31/506A61K31/513A61K31/704A61K33/24A61K38/17A61K38/45A61K38/47A61K47/6923A61K48/0008C12N15/113C12N15/1131C12Y204/02036C12Y302/02022C12N2310/14C12N2320/32A61K33/242A61K33/243A61P31/12A61P35/00A61P35/02A61K2300/00A61K47/50A61K9/209A61K49/08
Inventor C.E.阿什莉C.J.布林克尔E.C.卡恩斯M.H.菲克拉扎德L.A.费尔顿O.内格里特D.P.帕迪利亚B.S.威尔金森D.C.威尔金森C.L.威尔曼
Owner STC UNM
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