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The acidic microclimate in poly(lactide-co-glycolide) microspheres stabilizes camptothecins
Purpose. The camptothecin (CPT) analogue, 10-hydroxycamptothecin (10- HCPT) has been shown previously to remain in its acid-stable (and active) lactone form when encapsulated in poly(lactide-co-glycolide) (PLGA) microspheres (1). The purpose of this study was to determine the principal mechanism(s) of 10-HCPT stabilization. Methods. CPTs were encapsulated in PLGA 50:50 microspheres by standard solvent evaporation techniques. Microspheres were eroded in pH 7.4 buffer at 37°C. The ratio of encapsulated lactone to carboxylate was determined by HPLC as a function of time, initial form of drug encapsulated, fraction of co-encapsulated Mg(OH)2, CPT lipophilicity, and drug loading. Two techniques were developed to assess the microclimate pH, including: i) measurement of H+ content of the dissolved microspheres in an 80:20 acetonitrile/H2O mixture and ii) confocal microscopy of an encapsulated pH-sensitive dye, fluorescein. Results. The encapsulated carboxylate converted rapidly to the lactone after exposure to the release media, indicating the lactone is favored at equilibrium in the microspheres. Upon co-encapsulation of Mg(OH)2, the trend was reversed, i.e., the lactone rapidly converted to the carboxylate form. Measurement of - log(hydronium ion activity) (pa(H)/*) of dissolved microspheres with pH- electrode and pH mapping with fluorescein revealed the presence of an acidic microclimate. From the measurements of H+ and water contents of particles hydrated for 3 days, a microclimate pH was estimated to be in the neighborhood of 1.8. The co-encapsulation of Mg(OH)2 could both increase the pa(H)/* reading and neutralize pH in various regions of the microsphere interior. Varying the drug lipophilicity and loading revealed that the precipitation of the lactone could also stabilize CPT. Conclusions. PLGA microspheres prepared by the standard solvent evaporation techniques develop an acidic microclimate that stabilizes the lactone form of CPTs. This microclimate may be neutralized by co-encapsulating a base such as Mg(OH)2, as suggested by previous work with poly(ortho esters) (2).
Shenderova, Anna,Burke, Thomas G.,Schwendeman, Steven P.
p. 241 - 248
(1999)
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Preparation of 9-fluorocamptothecin derivative and application of 9-fluorocamptothecin derivative in antitumor aspect
The invention relates to preparation of 9-fluorocamptothecin compounds and application of the 9-fluorocamptothecin compounds in antitumor drugs. The structural formula of the compounds is shown in the specification. In-vitro antitumor activity screening results show that the compounds 9-fluorocamptothecin I and 7-ethyl-9-fluorocamptothecin II have broad-spectrum antitumor activity and have relatively strong inhibitory activity on cell lines of human liver cancer (HepG2), human ovarian cancer (A2780), human breast cancer (MCF7), human colon cancer (SW480) and human pancreatic cancer (SW1990), and IC50 values of the compounds 9-fluorocamptothecin I and 7-ethyl-9-fluorocamptothecin II are 0.10-0.77 mu M and 0.13-0.25 mu M respectively; particularly, the 7-ethyl-9-fluorocamptothecin II has a relatively strong inhibition effect on human ovarian cancer (A2780) cell lines and human colon cancer (SW480) cell lines, the IC50 of the 7-ethyl-9-fluorocamptothecin II on the human ovarian cancer (A2780) cell lines is 0.074 mu M, andthe IC50 of the 7-ethyl-9-fluorocamptothecin II on the human colon cancer (SW480) cell lines is 0.013 mu M , so that the 7-ethyl-9-fluorocamptothecin II is obviously superior to that of a control drug topotecan. Therefore, the 9-fluorocamptothecin compound is expected to be developed into a novel antitumor drug.
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Paragraph 0014-0018

(2022/01/12)

Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
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(2010/05/13)

Radiosynthesis of carbon-11-labeled camptothecin derivatives as potential positron emission tomography tracers for imaging of topoisomerase I in cancers
Four carbon-11-labeled camptothecin derivatives, 9-[11C]methoxy- 20(S)-camptothecin ([11C]5), 10-[11C]methoxy-20(S)- camptothecin ([11C]7), 9-nitro-10-[11C]methoxy-20(S)- camptothecin ([11C]9), and 9-[([11C]trimethylamino)methyl] -10-hydroxy-20(S)-camptothecin ([11C]11), have been synthesized as potential positron emission tomography tracers for imaging of topoisomerase I in cancers.
Gao, Mingzhang,Miller, Kathy D.,Sledge, George W.,Zheng, Qi-Huang
p. 3865 - 3869
(2007/10/03)

Process for the preparation of certain 9-substituted camptothecins
A process for the preparation of water soluble camptothecin analogs, including methods for the preparation of intermediates thereof, and the compounds prepared by said process. Water soluble camptothecin analogs are prepared which may be used for inhibiting the growth of tumor cells sensitive to such analogs.
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(2008/06/13)

Camptothecin analogues and methods of preparation thereof
Substituted analogues of camptothecin possessing cytotoxic activity towards cancer cells, of the general structure: STR1 wherein E is H, CO2 R, CONH2, CONHR, CONR2, or CN; R0 and R1 are independently the same or different and are H, or a linear or branched alkyl, linear or branched alkylaryl, hydroxyalkyl or aryl group; R2, R3 and R4 are independently the same or different and are H, or a linear or branched alkyl, linear or branched alkylaryl, hydroxyalkyl or aryl group; R5, R6, R7, R8 and R9 are independently the same or different and are H, or a linear or branched alkyl, linear or branched alkylaryl or aryl group, or an alkoxy, aryloxy, hydroxyalkyl, C-glycal, nitro, cyano or aminoalkoxy group, or CO2 R, Cl, F, Br, I, SR10, NR11 R12 or OR13 ; R is H, an alkyl, aryl, alkylaryl or hydroxyalkyl group; R10, R11 and R12 are independently the same or different and are H, an alkyl, aryl, alkylaryl or acyl group; R13 is glycosyl; and n is 0 or 1. Also provided are compositions comprising the analogues and methods of treating tumors as well as methods for preparing the analogues.
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(2008/06/13)

Methods of preparation of camptothecin analogs
Substituted analoguss of camptothecin possessing cytotoxic activity towards cancer cells, of the general structure: STR1 wherein E is H, CO2 R, CONH2, CONHR, CONR2, acyl, or CN; X is H OH, or OR; R1, R2, R3, and R4 are independently the same or different and are H, or a linear or branched chain alkyl, alkylaryl, or hydroxyalkyl group, or an aryl group; R5, R6, R7, R8, and R9 are independently the same or different and are H, or a linear or branched chain alkyl, alkylaryl, alkoxy, hydroxyalkyl, or aminoalkoxy group, or an aryl or aryloxy group, or a C-glycal, or CO2 R, nitro, cyano, Cl, F, Br, I, SR10, NR11 R12, or OR13 ; R is H, or a linear or branched chain alkyl, alkylaryl, or hydroxyalkyl group, or an aryl group; R10, R11 and R12 are independently the same or different and are H, or a linear or branched chain alkyl, alkylaryl, hydroxyalkyl, or acyl group, or an aryl group; R13 is glycosyl; n is 0 or 1; with the proviso that when R 1 is ethyl, and n is 0, E, R2, R3, and R4 are not all H. Intermediate compounds leading to the camptothecin analogues comprise substituted tricyclic compounds which consist of rings C, D, and E fused together. Methods for preparing the analoguss involve condensation of such intermediates with variably substituted protected α-aminobenzaldehydes.
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(2008/06/13)

Plant Antitumor Agents. 30. Synthesis and Structure Activity of Novel Camptothecin Analogs
A large number of camptothecin (CPT) analogs have been prepared in the 20S, 20RS, and 20R configurations with a number of ring A substituents.Topoisomerase I (T-I) inhibition data (IC50) have been obtained by standard procedures.In general, substitution at the 9 or 10 positions with amino, halogeno, or hydroxyl groups in compounds with 20S configuration results in compounds with enhanced T-1 inhibition.Compounds in the 20RS configuration were less active in vitro and in vivo and those in the 20R configuration were inactive.Compounds with 10,11-methylenedioxy substitution on ring A displayed a marked increase in potency in the T-I inhibition assay.The activities of some of the analogs as determined in a variety of in vivo assays including the L-1210 mouse leukemia assay were, in general, in accord with T-I inhibition.A number of water-soluble analogs such as 20-glycinate esters, 9-glycinamides, or hydrolyzed lactone salts were prepared and tested in in vitro and in vivo assays.In general, these compounds were less active than CPT both in terms of T-I inhibition and life prolongation in the L-1210 assay.However, certain 20-glycinate esters showed good in vivo activity after iv administration.
Wall, Monroe E.,Wani, Mansukh C.,Nicholas, Allan W.,Manikumar, Govindarajan,Tele, Chhagan,et al.
p. 2689 - 2700
(2007/10/02)

Synthesis and antitumor activity of 20(S)-camptothecin derivatives: A-ring modified and 7,10-disubstituted camptothecins
20(S)-Camptothecin derivatives having nitro, amino, chloro, bromo, hydroxyl and methoxyl groups in the A-ring were synthesized. B-Ring hydrogenated camptothecin (2a) was converted into 10-hydroxycamptothecin (6e) by treatment with lead tetraacetate in trifluoroacetic acid. 10-Substituted derivatives (6) were obtained by a photoreaction of N-oxides (9). The cytotoxicity of the A-ring modified camptothecins was evaluated against KB cells in vitro and leukemia L1210 in mice. 7-Ethyl-10-hydroxycamptothecin (6i) was identified as a potential derivative for further modification.
Sawada,Matsuoka,Nokata,Nagata,Furuta,Yokokura,Miyasaka
p. 3183 - 3188
(2007/10/02)

Camptothecin derivatives and process for preparing same
New Camptothecin derivatives possessing high anti-tumor activity with slight toxicity, represented by the general formula: STR1 wherein R1 is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxy group or an acyloxy group, R2 for a hydrogen atom, an alkyl group, an aralkyl group, a hydroxymethyl group, a carboxymethyl group or an acyloxymethyl group, and R3 is the grouping --XR' (where R' is a hydrogen atom, an alkyl group or an acyl group and X is an oxygen atom or a sulfur atom), a nitro group, an amino group, an alkylamino group, an acylamino group or a halogen atom, with the proviso that when both of R1 and R2 are hydrogen atoms, R3 should not be a hydroxyl group, methoxy group or acetoxy group. These new camptothecin derivatives are prepared by treating a 5-R1 -7-R2 -camptothecin derivative with a peroxidant and then reacting the resultant 5-R1 -7-R2 -camptothecin-1-oxide with an active hydrogen compound under irradiation of UV-rays or by catalytically hydrogenating the ring B of camptothecin in a solvent, treating the resultant tetrahydro product with an acylating agent, introducing a nitro group into the 10-position of the acylated product by the reaction with nitric acid, splitting off the acyl group in the 10-nitro product by hydrolysis and treating the hydrolyzed tetrahydro product with an oxidizing agent for dehydrogenation, and if desired, reducing the nitro group in the resulting product to an amino group and modifying the amino group by N-alkylation, N-acylation or by diazotization followed by hydrolysis or the Sandmeyer reaction, before or after the oxidation of the 10-nitro-tetrahydro product.
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(2008/06/13)