WO2021151450A1 - Targeted drug delivery system using bacterial ghosts of salmonella toward hepatic cancer cells - Google Patents
Targeted drug delivery system using bacterial ghosts of salmonella toward hepatic cancer cells Download PDFInfo
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- WO2021151450A1 WO2021151450A1 PCT/EG2020/000005 EG2020000005W WO2021151450A1 WO 2021151450 A1 WO2021151450 A1 WO 2021151450A1 EG 2020000005 W EG2020000005 W EG 2020000005W WO 2021151450 A1 WO2021151450 A1 WO 2021151450A1
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- dox
- bacterial ghosts
- ghosts
- loaded
- salmonella
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- 230000001580 bacterial effect Effects 0.000 title claims abstract description 35
- 241000607142 Salmonella Species 0.000 title claims abstract description 11
- 201000007270 liver cancer Diseases 0.000 title claims abstract description 11
- 208000014018 liver neoplasm Diseases 0.000 title claims abstract description 11
- 206010073069 Hepatic cancer Diseases 0.000 title claims abstract description 10
- 238000012377 drug delivery Methods 0.000 title claims abstract description 10
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims abstract description 30
- HPZOOQSXPMEJBV-ODCFVKFUSA-N Tirilazad mesylate Chemical compound CS(O)(=O)=O.O=C([C@@H]1[C@@]2(C)CC=C3[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)CN(CC1)CCN1C(N=1)=CC(N2CCCC2)=NC=1N1CCCC1 HPZOOQSXPMEJBV-ODCFVKFUSA-N 0.000 claims abstract description 12
- 229960004679 doxorubicin Drugs 0.000 claims abstract description 8
- 230000000694 effects Effects 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 5
- 230000008685 targeting Effects 0.000 claims description 5
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 230000001093 anti-cancer Effects 0.000 claims description 2
- 239000007853 buffer solution Substances 0.000 claims description 2
- 238000005119 centrifugation Methods 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 238000011534 incubation Methods 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 230000006907 apoptotic process Effects 0.000 abstract description 9
- 230000001028 anti-proliverative effect Effects 0.000 abstract description 6
- 239000002552 dosage form Substances 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 2
- 241000894006 Bacteria Species 0.000 abstract 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 abstract 1
- 238000002255 vaccination Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 15
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 210000000795 conjunctiva Anatomy 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- 238000001543 one-way ANOVA Methods 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 241001302654 Escherichia coli Nissle 1917 Species 0.000 description 2
- 241001293418 Mannheimia haemolytica Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 241001354013 Salmonella enterica subsp. enterica serovar Enteritidis Species 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
Definitions
- the technical field of this Invention is pharmaceutics and pharmaceutical pharmacy which is the science of dosage forms formulation.
- Bacterial ghosts are biological shells of walls and membranes of the bacterial cells that have punctured and evacuated from their internal cytoplasmic contents, such as functional proteins and most of the DNA material. Bacterial ghosts can be used in the medical and pharmaceutical fields. nowadays, they are used in some applications, for instance:
- the bacterial ghosts of recombinant E. coli Nissle 1917 that prepared genetically (E-lysis gene) have been targeted to conjunctiva -in-vitro- of Guinea pig and human.
- the bacterial ghosts of Mannheimia haemolytica, E. coli NK9373, E. coliNM522, and E. coli Nissle 1917 were targeted to human conjunctiva cells -in-vitro- and also they showed a very high adherence ability and picked up by the human cells very strongly. (6)
- the bacterial ghosts of Mannheimia haemolytica were prepared genetically and targeted toward human colorectal cancer cell line -in-vitro- and these ghosts were loaded with the anticancer drug-doxorubicin-DOX.
- the cancer cells showed a high picking up ability for these loaded ghosts and the antiproliferative activity of the DOX loaded ghosts was double incomparison to the free DOX which suggested less side effects of DOX the is highly toxic. (7)
- E-lysis gene The genetic method for preparation of bacterial ghosts (E-lysis gene) which is an expensive, uncommon and complicated method because of little knowledge about that gene. On the other hand, in this invention the simple and cheap chemical method has been used. (6)
- the prepared bacterial ghost didn’t uploaded by any drugs. Oppositely, the bacterial ghosts of Salmonella have uploaded by anticancer drug to be tested on the human hepatic cancer cells. (6)
- the bacterial ghosts of Salmonella enteritidis serovar typhim ATCC13311 were prepared using an easy, cheap and available method (tween 80 and lactic acid).
- the bacterial ghosts were used as a drug delivery system and both unman and animal vaccines.
- DOX loaded Salmonella ghosts were used for the first time as a drug delivery system to target the human hepatic cancer cells.
- the loading capacity was maximized to (27.5%) by incubating 10 mg of bacterial ghosts with 1 mg of free DOX for 10 minutes in pH 9 and room temperature (25 °C).
- In-vitro release study of DOX loaded BGs showed a sustained release (182 hours) and obeying Higuchi sustained kinetic release model.
- the death rate (tested by MTT assay) of HepG2 reached to 64.5% by using of 4 ⁇ g/ml (equivalent concentration), while it was about 51% using the same concentration of the free DOX (P value ⁇ 0.0001 One-way ANOVA analysis).
- the proliferative inhibitory concentration (IC50) of the DOX combined formula was 1.328 ⁇ g/ml that was about one third of the IC50 of the free DOX (3.374 ⁇ g/ml).
- the invention can be useful in the pharmaceutical industry field as a new dosage form to deliver doxorubicin to the human hepatic cancer cells - in-vitro- in a high efficiency and accuracy and this was because of the high bioadherence tendency of Salmonella bacteria on the liver cells which possibly will reduce the dangerous side effects of DOX. This also will need for clinical study.
- the invention can be executed as the following:
- the bacterial ghosts of Salmonella enteritidis serovar typhim ATCC13311 be prepared using the chemical method (tween 80 and lactic acid) the lyophilized
- DOX loaded bacterial ghosts be washed by a half normal saline (0.45%) two times and followed by centrifugation (4000 rpm) for two minutes in each time to extract the pure loaded ghosts.
- the washed ghosts be stored at 4 °C until be used in the targeting of hepatic cancer cells.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Bacterial ghosts are biological vehicles of dead and evacuated bacteria from their internal components which preserved the external characters. Recently, bacterial ghosts are considered as a biotechnology platform for some biomedical applications such as drug delivery systems and vaccination. In this invention, the loaded bacterial ghosts of Salmonella typhimurium with doxorubicin (DOX) were used as a targeted drug delivery system (dosage form) which loaded by application of specific conditions. The DOX loaded bacterial ghosts were targeted toward human hepatic cancer cell line (HepG2) in-vitro and achieved antiproliferative activity less than the free DOX by three folds, which suggests less DOX side effects. Additionally, the DOX loaded bacterial ghosts of Salmonella achieved about 91% apoptosis in hepatic cancer cells while the free DOX achieved about 39% apoptosis all in concentration of (1 µg/ml).
Description
Targeted Drug Delivery System Using Bacterial Ghosts of Salmonella toward Hepatic Cancer Cells
Technical Field
The technical field of this Invention is pharmaceutics and pharmaceutical pharmacy which is the science of dosage forms formulation.
Background Art:
Harnessing the bacterial ghosts as targeted drug delivery system. Bacterial ghosts are biological shells of walls and membranes of the bacterial cells that have punctured and evacuated from their internal cytoplasmic contents, such as functional proteins and most of the DNA material. Bacterial ghosts can be used in the medical and pharmaceutical fields. Nowadays, they are used in some applications, for instance:
1- Preparation of targeted drug delivery systems
2- Preparation of vaccines
3- Preparation of DNA delivery systems (1),(2)
Methods of preparation of bacterial ghosts:
First: the genetic method by induction of E- lysis protein gene to produce a tunnel through the cellular wall and membrane. (3)
Second: The chemical method, using two chemical agents (tween 80 and lactic acid) in a suitable concentrations and suitable times. This method has been used for preparation of the bacterial ghosts of Salmonella. (4)
Bacterial ghosts used before as a targeted drug delivery system in two different trials (none of both included targeting liver cancer cells).
The first trial:
The bacterial ghosts of recombinant E. coli Nissle 1917 that prepared genetically (E-lysis gene) have been targeted to conjunctiva -in-vitro- of Guinea pig and human. (5) The results showed high targeting and adherence of bacterial ghosts on the conjunctiva cells. In another similar study, the bacterial ghosts of Mannheimia haemolytica, E. coli NK9373, E. coliNM522, and E. coli Nissle 1917 were targeted to human conjunctiva cells -in-vitro- and also they showed a very high adherence ability and picked up by the human cells very strongly. (6)
The second trial:
The bacterial ghosts of Mannheimia haemolytica were prepared genetically and targeted toward human colorectal cancer cell line -in-vitro- and these ghosts were loaded with the anticancer drug-doxorubicin-DOX. The cancer cells showed a high picking up ability for these loaded ghosts and the antiproliferative activity of the DOX loaded ghosts was double incomparison to the free DOX which suggested less side effects of DOX the is highly toxic. (7)
The shortage in the previous art:
The first trial:
The genetic method for preparation of bacterial ghosts (E-lysis gene) has been used which is an expensive, uncommon and complicated method because of little knowledge about that gene. On the other hand, in this invention the simple and cheap chemical method has been used. (6)
The prepared bacterial ghost didn’t uploaded by any drugs. Oppositely, the bacterial ghosts of Salmonella have uploaded by anticancer drug to be tested on the human hepatic cancer cells. (6)
The second trial:
The genetic method for preparation of bacterial ghosts (E-lysis gene) has been used which is an expensive, uncommon and complicated method because of little knowledge about that gene. In this invention the simple and cheap chemical method has been used in preparation of Salmonella ghosts. The antiproliferative activity against the cancer cells was double while in this invention, the antiproliferative activity was triple. (7)
Disclosure of Invention:
The new in this invention:
- The bacterial ghosts of Salmonella enteritidis serovar typhim ATCC13311 were prepared using an easy, cheap and available method (tween 80 and lactic acid).
- The bacterial ghosts were loaded by DOX using an easy and applicable method.
- The loaded bacterial ghosts by DOX - in this invention- were targeted for the first time toward human hepatic cancer cells.
- The antiproliferative activity of the loaded bacterial ghosts with DOX were triple in comparison to the free DOX (Fig 1) and the resulted in high percentage of apoptosis (91%) (Fig 3)
The Details of the Invention:
As a new biotechnology platform which has different biomedical application, the bacterial ghosts were used as a drug delivery system and both unman and animal vaccines.
In this trial, the DOX loaded Salmonella ghosts were used for the first time as a drug delivery system to target the human hepatic cancer cells.
The loading capacity was maximized to (27.5%) by incubating 10 mg of bacterial ghosts with 1 mg of free DOX for 10 minutes in pH 9 and room temperature (25 °C). In-vitro release study of DOX loaded BGs showed a sustained release (182 hours) and obeying Higuchi sustained kinetic release model.
The death rate (tested by MTT assay) of HepG2 reached to 64.5% by using of 4 μg/ml (equivalent concentration), while it was about 51% using the same concentration of the free DOX (P value < 0.0001 One-way ANOVA analysis). The proliferative inhibitory concentration (IC50) of the DOX combined formula was 1.328 μg/ml that was about one third of the IC50 of the free DOX (3.374 μg/ml). Apoptosis analysis (tested by flowcytometry) showed more accumulation in early apoptosis (8.3%) and late apoptosis/necrosis (91%) by applying 1 μg/ml BG combined DOX, while 1 μg/ml free DOX showed 33.4% of cells in early apoptosis and 39.3% in late apoptosis/necrosis, (P value > 0.05: one-way ANOVA). (Fig 3).
The execution and method of exploitation of the invention:
The invention can be useful in the pharmaceutical industry field as a new dosage form to deliver doxorubicin to the human hepatic cancer cells - in-vitro- in a high efficiency and accuracy and this was because of the high bioadherence tendency of Salmonella bacteria on the liver cells which possibly will reduce the dangerous side effects of DOX. This also will need for clinical study.
The invention can be executed as the following:
1- The bacterial ghosts of Salmonella enteritidis serovar typhim ATCC13311 be prepared using the chemical method (tween 80 and lactic acid) the lyophilized
2- The prepared lyophilized bacterial ghosts of salmonella (10 mg) be incubated with 1 mg doxorubicin HCl for 10 minutes in a 10 ml TRIS HCl buffer solution in the room temperature (25°C).
3- The DOX loaded bacterial ghosts be washed by a half normal saline (0.45%) two times and followed by centrifugation (4000 rpm) for two minutes in each time to extract the pure loaded ghosts.
4- The washed ghosts be stored at 4 °C until be used in the targeting of hepatic cancer cells.
5- The clinical studies.
Brief description of the drawing :
Figure 1 :
IC50 of free DOX and BG-combined DOX ghost.
Figure 2:
The antiproliferative activities of different tested groups of different concentrations (0.5, 1, 2, and 4 μg/ml); free ghost, free DOX, C: BG- combined DOX in addition to the control group (5% DMEM), (One-way ANOVA) P value < 0.0001.
Figure 3:
The apoptosis and/or necrosis activities of: (A) control group (5%DMEM), (B) free ghost group (0.5 μg/ml), (C) free DOX (0.5 μg/ml), and (D) ghost combined DOX (0.5 μg/ml) on the HepG2 cells.
References:
1. Bacterial ghosts as drug carrier and targeting vehicles. Huter, Veronika , et al. 1999, Journal of Controlled Release, Vol. 61, pp. 51-63.
2. Bacterial ghosts: new challenges in medical and pharmaceutical applications. Khoshnoud, Saeed, Bahramian, Aghil and Goudarzi, Mehdi . 6, 2015, Intarnational Journal of Analytical, Pharmaceutical and Biomedical Sciences, Vol. 4, pp. 43-47.
3. Lubitz, Petra , Mayr, Ulrike Beate and Lubitz, Werner . Applications of Bacterial Ghosts in Biomedicine, [ed.] Carlos A. Guzman and Giora Z. Feuerstein. Pharmaceutical Biotechnology, s.l.: Landes Bioscience and Springer Science-Business Media, 2009, Vol. 655, 12, pp. 159-170.
4. Rabea, S., Salem-Bekhit, M. M., Alanazi, F. K., Yassin, A. S., Moneib, N.
A., & Hashem, A. E. M. (2018). A novel protocol for bacterial ghosts’ preparation using tween 80. Saudi Pharmaceutical Journal , 26(2), 232-237. https://doi.Org/10.1016/J.JSPS.2017.12.006
5. Montanaro, J., Inic-Kanada, A., Ladurner, A., Stein, E., Belij, S., Bintner, N., Barisani-Asenbauer, T. (2015). Escherichia coli Nissle 1917 bacterial ghosts retain crucial surface properties and express chlamydial antigen: An imaging study of a delivery system for the ocular surface. Drug Design, Development and Therapy, 9, 3741-3754. https://doi.org/10.2147/DDDT.S84370
6. Kudela, P., Roller, V. J., Mayr, U. B., Nepp, J., Lubitz, W., & Barisani- Asenbauer, T. (2011). Bacterial Ghosts as antigen and drug delivery system for ocular surface diseases: Effective internalization of Bacterial Ghosts by human conjunctival epithelial cells. Journal of Biotechnology, 153(3-4), 167- 175. https://doi.Org/10.1016/j.jbiotec.2011.03.022
7. Paukner, S., Kohl, G., & Lubitz, W. (2004). Bacterial ghosts as novel advanced drug delivery systems: Antiproliferative activity of loaded doxorubicin in human Caco-2 cells. Journal of Controlled Release, 94(1), 63- 74. https://doi.Org/10.1016/j.jconrel.2003.09.010
Claims
Claims:
1- The Claims:
This invention is characterized by the use of bacterial ghosts of Salmonella which prepared by an easy and simple chemical method and loaded by doxorubicin (anticancer) and used as a targeted drug delivery system avoiding most of the side effects of the drug.
2- The second claim:
According to the first claim, it is characterized by incubation of the lyophilized salmonella bacteria (10 mg) with 1 mg of free DOX in 10 ml TRIS HCl buffer solution for 10 minutes at room temperature (25°C).
3- The third claim:
According to the first or second claims, it is characterized by washing of the DOX loaded bacterial ghosts by a half normal saline (0.45%) two times and followed by centrifugation (4000 rpm) for two minutes in each time to extract the pure loaded ghosts.
4- The forth claim:
According to the first, second or third claims, it is characterized by that the washed ghosts be stored at 4 °C until be used in the targeting of hepatic cancer cells.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EG2020/000005 WO2021151450A1 (en) | 2020-01-29 | 2020-01-29 | Targeted drug delivery system using bacterial ghosts of salmonella toward hepatic cancer cells |
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|---|---|---|---|
| PCT/EG2020/000005 WO2021151450A1 (en) | 2020-01-29 | 2020-01-29 | Targeted drug delivery system using bacterial ghosts of salmonella toward hepatic cancer cells |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3195878A1 (en) * | 2016-01-22 | 2017-07-26 | Werner Lubitz | Bacterial ghosts for the treatment of cancer |
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- 2020-01-29 WO PCT/EG2020/000005 patent/WO2021151450A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3195878A1 (en) * | 2016-01-22 | 2017-07-26 | Werner Lubitz | Bacterial ghosts for the treatment of cancer |
Non-Patent Citations (3)
| Title |
|---|
| AFKHAMI-POUSTCHI, AMIN, MARYAM M. MATIN: "Use of Bacterial Ghosts as Novel Drug Delivery Systems to Improve Cancer Treatment", JOURNAL OF CELLULAR IMMUNOTHERAPY, vol. 2, no. l, February 2016 (2016-02-01), pages 8 - 11, XP055845390, DOI: 10.15562/tcp.11 * |
| SAMEH RABEA, SALEM-BEKHIT MOUNIR M., ALANAZI FARS K., YASSIN AYMEN S., MONEIB NAYERA A., HASHEM ABD ELGAWAD M.: "A novel protocol for bacterial ghosts' preparation using tween 80", SAUDI PHARMACEUTICAL JOURNAL, vol. 26, no. Issue 2, February 2018 (2018-02-01), pages 232 - 237, XP055845387, DOI: 10.1016/j.jsps.2017.12.006 * |
| SAMEH RABEA: "Targeting of Doxorubicin toward Primary Cancer of Hepatobiliary Cells Using Bacterial Ghost of Salmonella enterica serovar typhimurium", THESIS SUBMITTED IN PARTIAL FULFILLMENT OF DOCTORAL DEGREE IN PHARMACEUTICAL SCIENCES, 2019 * |
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