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Polymeric conjugates containing positively-charged moieties

A technology of polymers and compounds, applied in the directions of medical preparations containing active ingredients, organic active ingredients, ester active ingredients, etc., can solve the problems of unsatisfactory results and achieve the effect of improving cellular uptake

Inactive Publication Date: 2009-08-26
ENZON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Polymeric conjugates containing positively-charged moieties
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  • Polymeric conjugates containing positively-charged moieties

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Embodiment approach

[0248] The oligonucleotide can be, for example, an oligonucleotide having the same or substantially similar nucleotide sequence as Genasense (a / k / a oblimersen sodium (oblimersensodium), produced by Genta Inc., Berkeley Heights, NJ) acid. Genasense is an 18-polyphosphorothioate antisense oligonucleotide, TTCTCCCAGCGTGCGCCAT (SEQ ID NO: 6), which is complementary to the first six codons of the initiation sequence of human bcl-2 mRNA (human bcl-2 mRNA is the basis of this technology known in the art and described, for example, in US Patent 6,414,134 as SEQ ID NO: 19, incorporated herein by reference). The U.S. Food and Drug Administration (FDA) granted Orphan Drug status to Genasense in August 2000. Preferred embodiments include:

[0249] (i) Antisense Survivin LNA (SEQ ID NO: 3)

[0250] m C s -T s - m C s -A s -a s -t s -c s -c s -a s -t s -g s -g s - m C s -A s -G s -c;

[0251] The uppercase letters represent LNA, and "s" represents the phosphorothioate ...

Embodiment 1

[0481] Example 1. Compound 3:

[0482] To a solution of Compound 2 (10 mg, 1.7 μmol) in PBS buffer (5 mL, pH 7.8) was added Mal-PEG5k-NHS (100 mg, 17 μmol) from NOF Corporation and stirred at room temperature for 2 hours. The reaction mixture was diluted with water to 20 mL and loaded onto a Poros HQ, strong anion exchange column (10 mm x 1.5 mm, bed volume ~16 mL) with 20 mM Tris-HCl buffer, pH 7.0 (Buffer A) Pre-equilibrated. The column was washed with 3-4 column volumes of buffer A to remove excess PEG linker. The product was then eluted with a gradient of 0 to 100% 1 M NaCl in 20 mM Tris-HCl buffer (pH 7.0, buffer B) at a flow rate of 10 mL / min for 10 minutes, followed by 100% buffer B 10 minutes. The eluted product was desalted with HiPrep desalting column (50 mL) and lyophilized to obtain compound 3. Yield 6 mg (oligo equivalent, 60%).

Embodiment 2

[0483] Example 2. Compound 4:

[0484] To a solution of compound 3 in PBS buffer (6 mL, pH 7.0), peptide C-Tat (5 mg, 3 μmol) was added and stirred at room temperature for 2 hours. The reaction mixture was diluted to 20 mL with water and loaded onto a Resource S, strong cation exchange column (10 mm x 1.5 mm, column bed volume ~16 mL) with 100 mM K 2 HPO 4 , 5M urea buffer, pH 6.5 (buffer A) pre-equilibrated. The column was washed with 3-4 column volumes of buffer A to remove unreacted PEG-oligocompound. The product was then eluted with a gradient of 0 to 100% 2M KBr (buffer B) for 10 minutes at a flow rate of 10 mL / min, followed by 100% buffer B for 10 minutes. The eluted product was desalted with HiPrep desalting column (50 mL) and lyophilized to obtain compound 4. Yield 2 mg (oligomer equivalent, 30%).

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Abstract

The present invention provides polymeric conjugates containing positively charged moieties. Methods of making the polymeric delivery systems and methods of treating mammals using the same are also disclosed.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to the following U.S. Provisional Patent Applications serial numbers: 60 / 844,944 filed September 15, 2006, 60 / 844,945 filed September 15, 2006, 60 / 861,349 filed November 27, 2006, 60 / 861,350, filed November 27, 2006, 60 / 911,734, filed April 13, 2007, and 60 / 956,814, filed August 20, 2007, the contents of each of which are incorporated herein by reference. Background technique [0003] In the past, it has been determined that increasing the positive charge of polymers or conjugates comprising the same is beneficial when used in the delivery of biologically active moieties (eg, proteins, peptides, etc.). For example, commonly assigned US Patent No. 5,730,990 describes PEG and related polyalkylene oxides to which a single secondary or tertiary amine group is attached. The purpose of this combination is for the amine derivatized polymer to impart pi and / or pH adjustment to the conjugate. Th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/21A61K31/704A61K31/765A61K38/02A61K31/33
Inventor 赵洪普拉桑纳·雷迪伊万·霍拉克夏靖
Owner ENZON PHARM INC
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