Increased efficacy of doxorubicin delivered in multifunctional microparticles for mesothelioma therapy
Jedd M Hillegass1, Steven R Blumen, Kai Cheng
1Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405-0068, USA.
Abstract:
New and effective treatment strategies are desperately needed for malignant mesothelioma (MM), an aggressive cancer with a poor prognosis. We have shown previously that acid-prepared mesoporous microspheres (APMS) are nontoxic after intrapleural or intraperitoneal (IP) administration to rodents. The purpose here was to evaluate the utility of APMS in delivering chemotherapeutic drugs to human MM cells in vitro and in two mouse xenograft models of MM. Uptake and release of doxorubicin (DOX) alone or loaded in APMS (APMS-DOX) were evaluated in MM cells. MM cell death and gene expression linked to DNA damage/repair were also measured in vitro. In two severe combined immunodeficient mouse xenograft models, mice received saline, APMS, DOX or APMS-DOX injected directly into subcutaneous (SC) MM tumors or injected IP after development of human MMs peritoneally. Other mice received DOX intravenously (IV) via tail vein injections. In comparison to DOX alone, APMS-DOX enhanced intracellular uptake of DOX, MM death and expression of GADD34 and TP73. In the SC MM model, 3× weekly SC injections of APMS-DOX or DOX alone significantly inhibited tumor volumes, and systemic DOX administration was lethal. In mice developing IP MMs, significant (p < 0.05) inhibition of mesenteric tumor numbers, weight and volume was achieved using IP administration of APMS-DOX at one-third the DOX concentration required after IP injections of DOX alone. These results suggest APMS are efficacious for the localized delivery of lower effective DOX concentrations in MM and represent a novel means of treating intracavitary tumors.
Insights
Acid-prepared mesoporous microspheres (APMS) effectively deliver doxorubicin (DOX) to malignant mesothelioma (MM) cells. This novel drug delivery system shows promise for treating intracavitary tumors with lower effective drug concentrations.
Area of Science:
- Oncology
- Biomaterials Science
- Drug Delivery Systems
Background:
- Malignant mesothelioma (MM) is an aggressive cancer requiring novel treatment strategies.
- Acid-prepared mesoporous microspheres (APMS) have demonstrated safety for intrapleural and intraperitoneal administration.
- Effective localized chemotherapy delivery remains a challenge for MM treatment.
Purpose of the Study:
- To evaluate APMS as a vehicle for delivering doxorubicin (DOX) to human MM cells.
- To assess the efficacy of APMS-loaded DOX (APMS-DOX) in vitro and in vivo MM models.
- To investigate the impact of APMS-DOX on MM cell death and DNA damage-related gene expression.
Main Methods:
- In vitro studies: MM cell uptake, DOX release, cell death, and gene expression analysis.
- In vivo studies: Two severe combined immunodeficient mouse xenograft models of MM (subcutaneous and intraperitoneal).
- Administration routes: Subcutaneous, intraperitoneal (IP), and intravenous (IV) injections of APMS-DOX, DOX alone, or saline.
Main Results:
- APMS-DOX enhanced intracellular DOX uptake, MM cell death, and expression of GADD34 and TP73 compared to DOX alone.
- Subcutaneous injections of APMS-DOX significantly inhibited MM tumor volumes.
- Intraperitoneal administration of APMS-DOX achieved significant tumor inhibition at one-third the concentration of IP DOX alone, with reduced toxicity.
Conclusions:
- APMS are efficacious for localized delivery of lower doxorubicin concentrations in malignant mesothelioma.
- APMS represent a novel and effective strategy for treating intracavitary MM tumors.
- This approach offers a promising alternative to conventional chemotherapy with reduced systemic toxicity.
