Bacterially derived, intact minicells for delivery of therapeutic agents to brain tumors

A technology of microcells and brain tumors, which can be used in preparations for in vivo experiments, capsule delivery, anti-tumor drugs, etc., and can solve the problems of poor cure rate of brain cancer treatment

Pending Publication Date: 2019-01-04
ENGENEIC MOLECULAR DELIVERY PTY LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Despite Decades of Extensive Efforts, Cure Rates in Brain Cancer Treatment Are Terribly Poor

Method used

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  • Bacterially derived, intact minicells for delivery of therapeutic agents to brain tumors
  • Bacterially derived, intact minicells for delivery of therapeutic agents to brain tumors
  • Bacterially derived, intact minicells for delivery of therapeutic agents to brain tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0202] Example 1. Preparation of doxorubicin-coated minicells targeting canine EGFR

[0203] Minicells were derived from Salmonella typhi, a minCDE-chromosomal deletion mutant of S. typhimurium, purified, coated with doxorubicin (dox) and treated with bispecifics including anti-minicell surface O-glycan and anti-canine EGFR specificities Linked targeting of monoclonal antibodies (MAbs), (named EGFR microcell 阿霉素 ), as previously described by MacDiarmid et al. (2007).

[0204] Characterize first EGFR microcell 阿霉素 Their suitability for intravenous administration to seven dogs with advanced brain cancer (dogs designated BCD-1 to BCD-7). Two additional dogs, BCD-8 and BCD-9, presented to the veterinary care center but were not studied because of more advanced brain tumors and were euthanized. Brain biopsy samples provided respective brain tumor cells for in vitro studies.

Embodiment 2

[0205] Example 2. Characterization of anti-human EGFR monoclonal antibodies that bind to canine brain tumor cells

[0206] Upregulation and overexpression of EGFR is well known in -60% of GBM cases in humans (Smith et al., 2001) and dogs (Higgins et al., 2010). Given the non-availability of specific canine EGFR monoclonal antibodies, commercially available anti-human EGFR MAbs were tested in canine and human brain tumor cell lines to determine the cross-reactivity of the MAbs to EGFR on canine brain tumor cells.

[0207] Where feasible, brain tumor biopsy samples were obtained from case study dogs. Tissue samples from BCD-1, -8 and -9 were treated with 1 mg / ml in Dulbecco's modified Eagle's medium (DMEM) medium containing 10% fetal calf serum (FCS) and streptomycin Collagenase treatment for 10 min. Undigested tissue was removed by filtration through double sheets of sterile gauze. Collagenase digestion was stopped by diluting the cells with 5 ml of medium and centrifuging a...

Embodiment 3

[0216] Example 3. Determination of the sensitivity of canine brain cancer cells to the chemotherapeutic drug doxorubicin

[0217] Before treating dogs with advanced brain cancer with doxorubicin-encapsulated, EGFR-targeted minicells, it is important to determine whether canine brain tumor cells are sensitive or resistant to the chemotherapeutic drug doxorubicin.

[0218] Canine brain tumor cells BCD-1, -8, -9 and J3T and human brain tumor cell line U87-MG were inoculated in a 96-well plate, 5x 10 per well 3 cells. at 37°C, 5% CO 2 The next cells were incubated overnight.

[0219] Doxorubicin was added to the cells in 100 μL of relevant media containing serum concentrations ranging from 1.7 nM to 8,600 nM and incubated for 72 hours.

[0220] To measure the cytotoxic effect of doxorubicin, an MTS cell proliferation assay was performed. 20uL of MTS solution (CellTitre Aqueous One MTS reagent - Promega) was added to each well and incubated for 30 minutes in the dark. Absorb...

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Abstract

Systemic administration of intact, bacterially derived minicells results in rapid accumulation of the minicells in the microenvironment of a brain tumor, in therapeutically significant concentrations,without requiring endothelial endocytosis / transcytosis across the blood brain barrier or any other mechanism by which, pursuant to conventional approaches, nanoparticles have entered into that microenvironment. Accordingly, a wide variety of brain tumors, both primary and metastatic, can be treated by administering systemically a therapeutically effective amount of a composition comprised of a plurality of such minicells, each minicell being a vehicle for an active agent against the tumor, such as a radionuclide, a functional nucleic acid or a plasmid encoding one, or a chemotherapeutic agent.

Description

[0001] This application is a divisional application, the filing date of the original application is December 12, 2012, the application number is 2012800695921, and the title of the invention is "bacteria-derived, complete minicells for delivering therapeutic agents to brain tumors". [0002] Cross References to Related Applications [0003] This application claims priority to US Provisional Application Serial No. 61 / 569,907, filed December 13, 2011, the contents of which are hereby incorporated by reference in their entirety. Background technique [0004] Primary brain tumors consist of a diverse group of tumors derived from a number of different cell lines. According to the World Health Organization classification (Louis et al., 2007), tumors of the central nervous system are classified as astrocytic, oligodendrocytes, or a mixture thereof (oligoastrocytic). These tumors are further classified by subtype and graded from I to IV based on histology, with grade IV being the mos...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/50A61K47/46A61K45/00A61P35/00A61P35/04A61K51/12A61K47/68A61K31/713
CPCA61K9/5068A61K51/1203A61K47/6849A61P35/00A61P35/04A61P43/00A61P9/00A61K51/08A61K51/0491A61K51/1027A61K51/109A61K51/1045A61K47/6901A61K31/713A61K45/06A61K35/66A61K47/46
Inventor H·布拉姆巴特J·麦克迪尔米德
Owner ENGENEIC MOLECULAR DELIVERY PTY LTD
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