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Nanoscale carriers for the delivery or co-delivery of chemotherapeutics, nucleic acids and photosensitizers

A nanoscale, chemotherapeutic technology, applied in nanotechnology, nanotechnology, nanomedicine, etc., can solve problems such as limiting PDT efficacy, nucleic acid degradation, and short-lived nucleic acid effect.

Active Publication Date: 2016-08-17
UNIVERSITY OF CHICAGO +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite their potential in cancer therapy, nucleic acids such as small interfering RNA (siRNA) and microRNA (miRNA) may have limitations
First, these nucleic acids may be vulnerable to attack and degradation by enzymes that are ubiquitous in the environment, and second, the effects of nucleic acids such as siRNA and miRNA are often transient
Third, nucleic acids cannot enter cells by themselves, and existing delivery systems are either inefficient or unable to prolong circulation in vivo after systemic administration
However, despite their photochemical effectiveness for ROS production, they have suboptimal tumor accumulation after systemic administration, which may limit the efficacy of PDT in the clinic

Method used

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  • Nanoscale carriers for the delivery or co-delivery of chemotherapeutics, nucleic acids and photosensitizers
  • Nanoscale carriers for the delivery or co-delivery of chemotherapeutics, nucleic acids and photosensitizers
  • Nanoscale carriers for the delivery or co-delivery of chemotherapeutics, nucleic acids and photosensitizers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0243] Nanoscale coordination polymers with cisplatin or oxaliplatin and with electrostatic interaction on the particle surface RNA adsorbed on

[0244] 1.1. Synthesis of cisplatin prodrug (cisPtBp):

[0245]

[0246] Scheme 1. Structure of the bisphosphonate cisplatin prodrug.

[0247] The preparation of the bisphosphonate cisplatin prodrug, cisPtBp (Scheme 1) is described in International Application No. WO 2013 / 009701. More specifically, to cis,cis,trans-[Pt(NH 3 ) 2 Cl 2 (OH) 2 ] (0.5 g, 1.5 mmol) in 2 mL of dimethylformamide (DMF) was added containing 4 equivalents of diethoxyphosphinyl (diethoxyphosphinyl) isocyanate (0.92 mL, 6.0 mmol) in 1 mL of DMF solution. The resulting mixture was stirred at room temperature in the dark for 12 h. The solution was filtered and the resulting bisphosphonate complex was precipitated by adding diethyl ether and washed at least twice with diethyl ether to remove residual DMF. Yield: 80%. DMSO-d 6 middle 1 H NMR: δ8.61 (...

Embodiment 2

[0312] Chemotherapeutic agents loaded sequentially in porous nanoparticle coordination polymers

[0313]

[0314] Scheme 3. Cisplatin prodrug cis,cis,trans-[Pt(NH 3 ) 2 Cl 2 (OEt)(OCOCH 2 CH 2 COOH)] synthesis.

[0315] The cisplatin prodrug cis,cis,trans-[Pt(NH 3 ) 2 Cl 2 (OEt)(OCOCH 2 CH 2 COOH)]. More specifically, cisplatin was reacted with hydrogen peroxide in ethanol to provide an intermediate product with a hydroxyl group and one ethoxy ligand. The intermediate is then reacted with succinic anhydride to provide the prodrug.

[0316]

[0317] Scheme 4. Synthesis of amino-triphenyldicarboxylic acid (amino-TPDC) ligands.

[0318] Due to the high connectivity of SBU and the strong interaction between zirconium and oxygen, based on Zr 6(μ 3 -O) 4 (μ 3 -OH) 4 NCPs of secondary building units (SBU) and dicarboxylic acid bridging ligands are highly porous and stable in aqueous environments. This material is called UiO, after the original family discove...

Embodiment 3

[0325] Materials and methods for nanoparticle coordination polymers with photosensitizers and chemotherapeutic agents

[0326] 3.1. Materials, cell lines and animals:

[0327] Unless otherwise stated, all starting materials were purchased from Sigma-Aldrich Company (St.Louis, Missouri, United States of America) and Fisher (Thermo Fisher Scientific, Waltham, Massachusetts, United States of America), and used without further purification. 1,2-Dioleoyl-sn-glycero-3-phosphate sodium salt (DOPA), 1,2-distearoyl-sn-glycero-3-phosphorylcholine (DSPC), cholesterol and 1,2- Distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol) 2000] (DSPE-PEG2k) were both purchased from Avanti Polar Lipids (labaster, Alabama, United States of America).

[0328] Human head and neck cancer cell lines HNSCC135 (cisplatin-sensitive), SCC61 (cisplatin-sensitive), JSQ3 (cisplatin-resistant) and SQ20B (cisplatin-resistant) were developed by Dr. Stephen J. Kron (Department of Molecular ...

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Abstract

Nanoscale coordination polymer nanoparticles for the co-delivery of multiple therapeutic agents are described. The multiple therapeutic agents can include a combination of different chemotherapeutic agents, a combination of one or more chemotherapeutic agents and one or more nucleic acids, such as small interfering RNA (siRNA) or microRNA, a combination of one or more chemotherapeutic agents and a photosensitizer (i.e., for use in photodynamic therapy), or a plurality of different siRNAs. Pharmaceutical formulations including the nanoparticles, methods of using the nanoparticles to treat cancer, and methods of making the nanoparticles are also described.

Description

[0001] related application [0002] The subject matter of the present disclosure claims priority to US Provisional Patent Application Serial No. 61 / 900,698, filed November 6, 2013; the entire disclosure of which is hereby incorporated by reference in its entirety. [0003] Government interests [0004] This invention was made with government support under Grant No. U01-CA151455 awarded by the National Institutes of Health. The government has certain rights in this invention. technical field [0005] The subject matter of the present disclosure provides a nanocarrier platform based on metal organic matrix materials, such as nanoscale coordination polymer (coordination polymer) (NCP) (comprising metal organic framework (skeleton, frameworks) (MOF) or nanoscale metal organic framework ( NMOF)) for co-delivery of two or more therapeutic agents. In some embodiments, the platform is used for co-delivery of chemotherapeutics (e.g., small molecule and / or non-nucleic acid chemothera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/14C12N15/11
CPCC12N15/111C12N2310/11C12N2310/14C12N2310/141C12N2320/31C12N2320/32A61K45/06A61K9/1271A61P35/00A61P43/00B82Y5/00A61K31/664A61K31/713C12N15/113
Inventor 林文斌何春柏刘德敏
Owner UNIVERSITY OF CHICAGO
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