Microspheres targeted with a mesothelin antibody and loaded with doxorubicin reduce tumor volume of human mesotheliomas in xenografts

Our plain-English summary of Microspheres targeted with a mesothelin antibody and loaded with doxorubicin reduce tumor volume of human mesotheliomas in xenografts, by S.L. Macura, J.L. Steinbacher, M.B. Macpherson, et al (BMC Cancer, 2013).

The study

• Authors: S.L. Macura, J.L. Steinbacher, M.B. Macpherson, M.J. Lathrop, M. Sayan, J.M. Hillegass, S.L. Beuschel, T.N. Perkins, P.C. Spiess, A. van der Vliet, K.J. Butnor, A. Shukla, M. Wadsworth, C.C. Landry, B.T. Mossman
• Journal: BMC Cancer
• Published: 2013;13:400
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant mesotheliomas (MMs) are chemoresistant tumors related to exposure to asbestos fibers. The long latency period of MM (30-40 yrs) and heterogeneity of tumor presentation make MM difficult to diagnose and treat at early stages. Currently approved second-line treatments following surgical resection of MMs include a combination of cisplatin or carboplatin (delivered systemically) and pemetrexed, a folate inhibitor, with or without subsequent radiation. The systemic toxicities of these treatments emphasize the need for more effective, localized treatment regimens.

Methods: Acid-prepared mesoporous silica (APMS) microparticles were loaded with doxorubicin (DOX) and modified externally with a mesothelin (MB) specific antibody before repeated intraperitoneal (IP) injections into a mouse xenograft model of human peritoneal MM. The health/weight of mice, tumor volume/weight, tumor necrosis and cell proliferation were evaluated in tumor-bearing mice receiving saline, DOX high (0.2 mg/kg), DOX low (0.05 mg/kg), APMS-MB, or APMS-MB-DOX (0.05 mg/kg) in saline.

Results: Targeted therapy (APMS-MB-DOX at 0.05 mg/kg) was more effective than DOX low (0.05 mg/kg) and less toxic than treatment with DOX high (0.2 mg/kg). It also resulted in the reduction of tumor volume without loss of animal health and weight, and significantly decreased tumor cell proliferation. High pressure liquid chromatography (HPLC) of tumor tissue confirmed that APMS-MB-DOX particles delivered DOX to target tissue.

Conclusions: Data suggest that targeted therapy results in greater chemotherapeutic efficacy with fewer adverse side effects than administration of DOX alone. Targeted microparticles are an attractive option for localized drug delivery.

In plain English

This was a laboratory experiment in mice. It did not study people or asbestos exposure. The authors injected human peritoneal mesothelioma cells into the abdomens of immune-deficient (SCID) mice. After four weeks of tumor growth, groups of six mice received abdominal injections three times a week. The groups got saline, plain doxorubicin (a chemotherapy drug) at a high dose (0.2 mg/kg) or a low dose (0.05 mg/kg), silica microparticles coated with an antibody to mesothelin (a protein on mesothelioma cells), or the same particles loaded with low-dose doxorubicin. Two saline mice developed no tumors. Compared with saline, low-dose doxorubicin and empty particles, both the drug-loaded particles and high-dose doxorubicin reduced average tumor volume. Only the high-dose group lost significantly more body weight. In small free-floating tumors, the drug-loaded particles significantly lowered the share of dividing cells. Differences in dead tumor tissue were not statistically significant. Doxorubicin levels in tumors were not significantly different between low-dose plain drug and drug-loaded particles. The authors concluded that this targeting allowed doxorubicin doses to be cut about 4-fold without side effects or toxicity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: animal experiment (mouse xenograft model of human peritoneal malignant mesothelioma)
• Who was studied: Severe combined immunodeficient (SCID) mice, each injected intraperitoneally with 1 million HMESO human mesothelioma cells. There were 5 treatment groups of 6 mice each. Two saline-group mice did not develop tumors, so 4 saline mice were analyzed. The work was done at the University of Vermont.
• Exposure: No asbestos exposure was studied. The mice were given intraperitoneal injections 3 times per week for 3 weeks (8 injections in total) of one of the following: saline; doxorubicin alone at 0.2 mg/kg (high) or 0.05 mg/kg (low); acid-prepared mesoporous silica (APMS) microparticles carrying a mesothelin antibody (APMS-MB) with no drug; or APMS-MB loaded with doxorubicin at 0.05 mg/kg (APMS-MB-DOX).
• Main results:
  • Average tumor volume was significantly reduced (p less than or equal to 0.05) in the APMS-MB-DOX (0.05 mg/kg) group compared with the saline, DOX low and APMS-MB groups. The same reduction was seen in the DOX high (0.2 mg/kg) group.
  • The text reports that average tumor weight was significantly reduced in the DOX high and APMS-MB-DOX groups compared with saline controls.
  • The DOX high (0.2 mg/kg) group lost weight over time at a significantly different rate from all other groups. No significant weight differences were found among the other groups.
  • Bloody peritoneal fluid was seen in the DOX high and DOX low groups, but not in the APMS-MB-DOX group.
  • In mesenteric tumors, the average share of dead (necrotic) tissue was 65% in the saline group, 53% in the DOX low group and 41% in the APMS-MB-DOX group. These differences were not statistically significant. In spheroid tumors, necrosis was roughly 20-25% in all groups.
  • In spheroid tumors, APMS-MB-DOX significantly reduced the share of dividing (Ki-67-positive) cells compared with saline controls and with DOX low. No significant change was seen in mesenteric tumors.
  • Doxorubicin was found in tumor tissue at 2.47 nmoles/gm in the DOX low group and 2.57 nmoles/gm in the APMS-MB-DOX group.
  • The tumor doxorubicin levels did not differ significantly between the DOX low and APMS-MB-DOX groups. Doxorubicin was not detected in peritoneal fluid in either group.
  • Compared with the saline group, the percentage of macrophages in peritoneal fluid was significantly higher in all treatment groups, and neutrophils were significantly lower.
• The authors' conclusion: The authors concluded that the mesothelin-targeted microparticles (APMS-MB-DOX, 0.05 mg/kg) worked better than the same dose of doxorubicin alone and reduced the side effects seen with high-dose doxorubicin. They stated that effective doxorubicin doses could be reduced about 4-fold without side effects or toxicity.
• Limitations the authors state:
  • Staining for tumor-associated macrophage types was done only in the saline and APMS-MB groups and was not quantified. The authors said further quantitative studies are planned in all treatment groups.
  • The authors said future experiments are needed to examine the effect of multiple doses of APMS-MB-DOX.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelin, Doxorubicin, Mesothelioma, Malignant Mesothelioma, Latency, Surgical Resection, Cisplatin, Carboplatin.

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• Targeting a membrane-proximal epitope on mesothelin increases the tumoricidal activity of a bispecific antibody blocking CD47 on mesothelin-positive tumors — E. Hatterer, X. Chauchet, et al. (2020)
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• A human single-domain antibody elicits potent antitumor activity by targeting an epitope in mesothelin close to the cancer cell surface — Z. Tang, M. Feng, et al. (2013)
• Preclinical Efficacy of an Antibody-Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET — A.G. Terwisscha van Scheltinga, A. Ogasawara, et al. (2017)

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