ITMI991243A1 - EXTRACTABLE PROTEIN FROM LIVER OF MAMMALS FOR ANTI-CANCER ACTIVITY - Google Patents
EXTRACTABLE PROTEIN FROM LIVER OF MAMMALS FOR ANTI-CANCER ACTIVITY Download PDFInfo
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- ITMI991243A1 ITMI991243A1 IT1999MI001243A ITMI991243A ITMI991243A1 IT MI991243 A1 ITMI991243 A1 IT MI991243A1 IT 1999MI001243 A IT1999MI001243 A IT 1999MI001243A IT MI991243 A ITMI991243 A IT MI991243A IT MI991243 A1 ITMI991243 A1 IT MI991243A1
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- protein
- liver
- mammals
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- 102000004169 proteins and genes Human genes 0.000 title claims description 20
- 108090000623 proteins and genes Proteins 0.000 title claims description 20
- 210000004185 liver Anatomy 0.000 title claims description 13
- 241000124008 Mammalia Species 0.000 title description 3
- 230000001093 anti-cancer Effects 0.000 title 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 210000004881 tumor cell Anatomy 0.000 claims description 6
- 231100000433 cytotoxic Toxicity 0.000 claims description 5
- 230000001472 cytotoxic effect Effects 0.000 claims description 5
- 241000283707 Capra Species 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000008366 buffered solution Substances 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- 238000010828 elution Methods 0.000 claims description 2
- 230000001939 inductive effect Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 229940041181 antineoplastic drug Drugs 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 239000007983 Tris buffer Substances 0.000 description 7
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 7
- 239000008118 PEG 6000 Substances 0.000 description 4
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007402 cytotoxic response Effects 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229940040511 liver extract Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 239000000439 tumor marker Substances 0.000 description 1
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Descrizione dell'invenzione industriale avente per titolo: Description of the industrial invention entitled:
"PROTEINA ESTRAIBILE DA FEGATO DI MAMMIFERI AD ATTIVITÀ' ANTITUMORALE" "EXTRACTABLE PROTEIN FROM MAMMALS LIVER WITH ANTI-TUMOR ACTIVITY"
La presente invenzione ha per oggetto una proteina di circa 90 kDa estraibile da fegato di mammiferi in condizioni non acide e capace di indurre anticorpi citossici verso cellule tumorali. The present invention relates to a protein of about 90 kDa extractable from mammalian liver under non-acidic conditions and capable of inducing cytoxic antibodies to tumor cells.
Proteine ad attività antitumorale estraibili con acidi forti da fegato di mammiferi, in particolare da fegato di capra, sono state descritte in WO92/10197 Proteins with strong acid extractable antitumor activity from mammalian liver, in particular from goat liver, have been described in WO92 / 10197
F., Botta, M., Ferrara, R., Bailo, M., Biancardi, C., Cavalca, V., Arzani, C., and Maraschin, R., (1994). Toxicological and anti-tumoral activity of UK101, a mammalian liver extract. J.Tumor Marker Oncol. 9, 49-56) che hanno dimostrato la loro capacità di indurre citotossicità mediata da anticorpi di tipo IgG e IgM verso linee cellulari tumorali. Anticorpi diretti contro la proteina UK114 sono in grado di legarsi ad antigeni espressi sulla superficie di cellule tumorali di specie diverse. F., Botta, M., Ferrara, R., Bailo, M., Biancardi, C., Cavalca, V., Arzani, C., and Maraschin, R., (1994). Toxicological and anti-tumoral activity of UK101, a mammalian liver extract. J.Tumor Marker Oncol. 9, 49-56) which have demonstrated their ability to induce cytotoxicity mediated by IgG and IgM antibodies to tumor cell lines. Antibodies directed against the UK114 protein are able to bind to antigens expressed on the surface of tumor cells of different species.
Prove immunocitochimiche e di citotossicità effettuate con le proteine acido solubili sopra citate hanno suggerito tuttavia la presenza di altri antigeni che potrebbero essere il bersaglio degli effetti citotossici riscontrati in vitro e in vivo . Immunocytochemical and cytotoxicity tests carried out with the acid-soluble proteins mentioned above, however, suggested the presence of other antigens that could be the target of the cytotoxic effects found in vitro and in vivo.
Si è ora trovato un antigene di circa 90 kDa in SDS-PAGE estraibile da fegato di mammiferi che è in grado di indurre, se somministrato a pazienti o animali portatori di tumori, una marcata risposta citotossica nei confronti di cellule tumorali . An antigen of about 90 kDa has now been found in SDS-PAGE extractable from mammalian liver which is able to induce, if administered to patients or animals carrying tumors, a marked cytotoxic response towards tumor cells.
La proteina dell’invenzione, indicata di seguito per brevità semplicemente come proteina 90 kDa, è ottenibile in particolare per estrazione del fegato di mammiferi con soluzioni tamponate a pH 7.4 (PBS) seguita da precipitazione con polietilenglicol 6000 al 15%, cromatografia su TSK-DEAE a pH 8, eluizione con NaCl 0.3M e purificazione su TSK SW3000. The protein of the invention, hereinafter referred to simply as 90 kDa protein, is obtainable in particular by extraction of mammalian liver with buffered solutions at pH 7.4 (PBS) followed by precipitation with 15% polyethylene glycol 6000, chromatography on TSK- DEAE at pH 8, elution with 0.3M NaCl and purification on TSK SW3000.
Il processo dell’estrazione e della purificazione della proteina dell’invenzione è illustrato nell’allegata figura. The process of extraction and purification of the protein of the invention is illustrated in the attached figure.
Preferibilmente, si utilizza fegato di capra ma si possono impiegare fegati di altri mammiferi (ad esempio di suini, bovini, equini o altri ovini) . Goat liver is preferably used but the livers of other mammals (for example pigs, cattle, horses or other sheep) can be used.
La proteina 90 kDa così ottenuta può essere impiegata nella immunoterapia di tumori, essendo in grado di indurre la formazione di anticorpi citotossici nei confronti di cellule di tumori umani, in particolare di carcinomi e adenocarcinomi. The 90 kDa protein thus obtained can be used in tumor immunotherapy, being able to induce the formation of cytotoxic antibodies against human tumor cells, in particular carcinomas and adenocarcinomas.
La citotossicità è qualificabile in vitro su cellule Jurkat e Kato III utilizzando metodi convenzionali, basati ad esempio all'uso di kit commerciali quali il kit CDCpK (Pharmaproduct). In particolare, si notava la comparsa di citotossicità nel siero di conigli già dopo un primo trattamento con proteina 90 kDA (1 mg/animale in soluzione fisiologica) su cellule Jurkat e Kato III. Cytotoxicity can be qualified in vitro on Jurkat and Kato III cells using conventional methods, based for example on the use of commercial kits such as the CDCpK (Pharmaproduct) kit. In particular, the appearance of cytotoxicity in the serum of rabbits was noted already after a first treatment with protein 90 kDA (1 mg / animal in physiological solution) on Jurkat and Kato III cells.
L’invenzione riguarda pertanto anche composizioni farmaceutiche contenenti come ingrediente attivo una dose efficace della proteina 90 kDa. The invention therefore also relates to pharmaceutical compositions containing an effective dose of the 90 kDa protein as an active ingredient.
Le composizioni dell’invenzione potranno essere somministrate utilizzando le vie di somministrazione convenzionali per proteine e polipeptidi, ad esempio la via sottocutanea o intramuscolare. Il trattamento può essere ripetuto ed è preferibile un trattamento che prevede somministrazioni distanziate di una-due settimane di dosi comprese tra 0.1 e 20 mg di proteina 90 kDA. The compositions of the invention can be administered using the conventional routes of administration for proteins and polypeptides, for example the subcutaneous or intramuscular route. The treatment can be repeated and a treatment involving one to two weeks spaced doses of doses ranging from 0.1 to 20 mg of 90 kDA protein is preferable.
Si è inoltre sorprendentemente trovato che è possibile indurre elevata citotossicità anche somministrando la proteina a dosaggi molto bassi, dell'ordine di 1.104 - 1.1010 g, per via sublinguale, sotto forma di granuli o gocce di soluzioni o sospensioni idroalcoliche all' 1 % di etanolo, con concentrazioni di principio attivo variabili da IO'6 a 10 10 M. It has also surprisingly been found that it is possible to induce high cytotoxicity even by administering the protein at very low dosages, of the order of 1.104 - 1.1010 g, sublingually, in the form of granules or drops of hydroalcoholic solutions or suspensions of 1% ethanol. , with concentrations of active principle ranging from 10'6 to 10 10M.
Il seguente esempio illustra l’invenzione in maggior dettaglio. _ The following example illustrates the invention in greater detail. _
ESEMPIO EXAMPLE
Estrazione Extraction
50 gr di fegato di capra vengono omogenati e ripresi ad un volume finale con 400 mi di PBS 0.01 M Ph 7.2. 50 g of goat liver are homogenized and taken up to a final volume with 400 ml of PBS 0.01 M Ph 7.2.
51 agita per 30 minuti a 4°C e si centrifuga su JA14 a 14.000 RPM per 30 minuti. 51 shake for 30 minutes at 4 ° C and centrifuge on JA14 at 14,000 RPM for 30 minutes.
Si filtra su bukner; 1.2 μm finale si 0.45 pm. It filters on bukner; 1.2 μm final yes 0.45 pm.
Volume: 340 mi conc. 10.9 mg/ml. Volume: 340 mi conc. 10.9 mg / ml.
Precipitazione frazionata PEG 6000. Fractional precipitation PEG 6000.
I 336 mi del campione sopraindicato, vengono trattati con PEG 6000 in polvere al 5% (16.8g). The 336 ml of the aforementioned sample are treated with 5% PEG 6000 in powder (16.8g).
Agitando per 1 ora a 4°C. Si centrifuga su J 6 a 4000 g per 30'. Shaking for 1 hour at 4 ° C. It is centrifuged on J 6 at 4000 g for 30 '.
II pellet viene ripreso con 61 mi di Tris/HCl 0.03 M pH 8, mentre il surnatante (340 mi) viene riprecipitato con PEG 6000 al 5% (17 g), quindi 10% finale agitando per 1 ora a 4°C. The pellet is taken up with 61 ml of Tris / HCl 0.03 M pH 8, while the supernatant (340 ml) is re-precipitated with PEG 6000 at 5% (17 g), then 10% final by stirring for 1 hour at 4 ° C.
Si centrifuga su J6 a 4000 g per 30' e si riprende il pellet con 62 mi di Tris/HCl 0.03 M pH8. It is centrifuged on J6 at 4000 g for 30 'and the pellet is taken up with 62 ml of Tris / HCl 0.03 M pH8.
Il surnatante 345 mi viene trattato con PEG 6000 al 5% (17.25 g) quindi finale 15%, agitando per 1 ora a 4°C. The supernatant 345 ml is treated with PEG 6000 at 5% (17.25 g) then final 15%, stirring for 1 hour at 4 ° C.
Si centrifuga su J6 a 4000 g per 30'. It is centrifuged on J6 at 4000 g for 30 '.
II surnatante viene eliminato, mentre il pellet viene ripreso con 200 mi di Tris/HCl 0.03 M pH8. The supernatant is removed, while the pellet is taken up with 200 ml of Tris / HCl 0.03 M pH8.
Pellet PEG 5% volume: 61 mi conc. 9.34 mg/ml. Pellet PEG 5% volume: 61 ml conc. 9.34 mg / ml.
Pellet PEG 10% volume: 62 mi conc. 13 mg/ml. Pellet PEG 10% volume: 62 ml conc. 13 mg / ml.
Pellet PEG 15% volume: 200 mi conc. 3.38 mg/ml. Pellet PEG 15% volume: 200 ml conc. 3.38 mg / ml.
DEAE - Sephacell DEAE - Sephacell
Circa 150 mi di resina DEAE-S. vengono equilibrati in tampone Tris/HCl 0.03 M pH 8. Approximately 150 ml of DEAE-S resin. they are equilibrated in Tris / HCl 0.03 M pH 8 buffer.
Si incuba la resina con il compione PEG 15% per 30 minuti a t.a. 200 mi di lavaggio. The resin is incubated with the 15% PEG composition for 30 minutes at rt. 200 ml of washing.
LEG 1: 200 mi Tris/HCl 0.5 M pH 8 per 30 minuti a t.a. 200 mi di lavaggio. LEG 1: 200 ml Tris / HCl 0.5 M pH 8 for 30 minutes at rt 200 ml of washing.
LEG 2: 200 mi Tris/HCl 0.03 M pH 8 0.3 M NaCl per 30 minuti a t.a. 200 mi di lavaggio. LEG 2: 200 ml Tris / HCl 0.03 M pH 8 0.3 M NaCl for 30 minutes at rt 200 ml of washing.
LEG 3: 200 mi Tris/HCl 0.03 M pH 8 1 M NaCl per 30 minuti a t.a. 200 mi di lavaggio. LEG 3: 200 ml Tris / HCl 0.03 M pH 8 1 M NaCl for 30 minutes at rt 200 ml of washing.
Si ottengono così i seguenti campioni: The following samples are obtained:
S.B. volume: circa 400 mi conc: 294 γ/ml. S.B. volume: about 400 ml conc: 294 γ / ml.
LEG 1 volume: circa 400 mi conc: 1.14 γ/ml. LEG 1 volume: about 400 ml conc: 1.14 γ / ml.
LEG 2 volume: circa 400 mi conc: su PM 30. LEG 2 volume: about 400 mi conc: on PM 30.
LEG 3 volume: circa 400 mi conc: 137 γ/ml. LEG 3 volume: about 400 ml conc: 137 γ / ml.
Il LEG 2 viene conc. su PM 30 ad un volume finale di circa 20 mi alla conc. di circa 3.6 mg/ml. LEG 2 is conceded. on PM 30 to a final volume of about 20 ml at conc. of about 3.6 mg / ml.
SW3000 prep. SW3000 prep.
Il LEG 2 da DEAE-S. sopracitato, viene purificato in SW3000 prep. (10 cariche da 2 mi). The LEG 2 by DEAE-S. mentioned above, it is purified in SW3000 prep. (10 charges of 2 ml).
Si eluiscono quattro frazioni, la seconda delle quali viene concentrata su PM 30 e dializzata contro HzO a vol. finale di circa 2 ml alla conc. di circa 1.5 mg/ml Four fractions are eluted, the second of which is concentrated on PM 30 and dialyzed against HzO at vol. final of about 2 ml at the conc. of about 1.5 mg / ml
Claims (6)
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT1999MI001243 IT1312341B1 (en) | 1999-06-03 | 1999-06-03 | 10-Formyltetrahydrofolate dehydrogenase, useful as a therapeutic agent, particularly as an antitumor agent possessing high cytotoxicity |
| AU59695/00A AU5969500A (en) | 1999-06-03 | 2000-06-02 | 10-formyltetrahydrofolate dehydrogenase as therapeutical agent |
| JP2001501245A JP2003501398A (en) | 1999-06-03 | 2000-06-02 | 10-formyltetrahydrofolate dehydrogenase as therapeutic agent |
| PCT/EP2000/005066 WO2000074711A2 (en) | 1999-06-03 | 2000-06-02 | 10-formyltetrahydrofolate dehydrogenase as therapeutical agent |
| EP00945698A EP1181046B1 (en) | 1999-06-03 | 2000-06-02 | 10-formyltetrahydrofolate dehydrogenase as therapeutical agent |
| ES00945698T ES2204649T3 (en) | 1999-06-03 | 2000-06-02 | `10-FORMILTETRAHYDROPHOLATE DEHYDROGENASE AS A THERAPEUTIC AGENT. |
| DE60004819T DE60004819T2 (en) | 1999-06-03 | 2000-06-02 | 10-FORMYLTETRAHYDROFOLATE DEHYDROGENASE AS A THERAPEUTIC AGENT |
| AT00945698T ATE247976T1 (en) | 1999-06-03 | 2000-06-02 | 10-FORMYLTETRAHYDROFOLATE DEHYDROGENASE AS A THERAPEUTIC AGENT |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT1999MI001243 IT1312341B1 (en) | 1999-06-03 | 1999-06-03 | 10-Formyltetrahydrofolate dehydrogenase, useful as a therapeutic agent, particularly as an antitumor agent possessing high cytotoxicity |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| ITMI991243A0 ITMI991243A0 (en) | 1999-06-03 |
| ITMI991243A1 true ITMI991243A1 (en) | 2000-12-03 |
| IT1312341B1 IT1312341B1 (en) | 2002-04-15 |
Family
ID=11383109
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT1999MI001243 IT1312341B1 (en) | 1999-06-03 | 1999-06-03 | 10-Formyltetrahydrofolate dehydrogenase, useful as a therapeutic agent, particularly as an antitumor agent possessing high cytotoxicity |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | IT1312341B1 (en) |
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1999
- 1999-06-03 IT IT1999MI001243 patent/IT1312341B1/en active
Also Published As
| Publication number | Publication date |
|---|---|
| ITMI991243A0 (en) | 1999-06-03 |
| IT1312341B1 (en) | 2002-04-15 |
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