Tissue Penetration and Activity of Camptothecins in Solid Tumor Xenografts

Abstract

The ability of a panel of camptothecin derivatives to access the tumor compartment was evaluated to determine the mechanisms by which the architecture of solid tumors may act to limit their activity. Microregional localization and activity of members of the camptothecin class of topoisomerase I targeting agents, including topotecan, irinotecan, and irinophore C, a lipid-based nanoparticulate formulation of irinotecan, were evaluated over time in HCT116 and HT29 colorectal tumor xenografts. Using native drug fluorescence, their distributions in tissue cryosections were related to the underlying tumor vasculature, tumor cell proliferation, and apoptosis. Topotecan exhibited a relatively uniform tumor distribution; in tissue 100 mm away from vessels, it reached 94% AE 5% of levels seen around blood vessels, whereas irinotecan and irinophore C were found to reach only 41% AE 10% and 5% AE 2%, respectively. Surprisingly, all three agents were able to initially inhibit proliferation uniformly throughout the tumors, and it was their rate of washout (topotecan > irinotecan > irinophore C) that correlated with activity. To explain this discrepancy, we looked at SN38, the active metabolite of irinotecan, and found it to penetrate tissue similarly to topotecan. Hence, the poor access to the tumor compartment of irinotecan and irinophore C could be offset by their systemic conversion to SN38. It was concluded that all three agents were effective at reaching tumor cells, and that despite the poor access to the extravascular compartment of irinophore C, its extended plasma exposure and systemic conversion to the diffusible metabolite SN38 enabled it to effectively target solid tumors.

Tumor-Targeting, MicroRNA-Silencing Porous Silicon Nanoparticles for Ovarian Cancer Therapy

“…The level of caspase-3 activity was comparable to the level observed from cells treated with camptothecin, a pro-apoptotic drug commonly used as a positive control in caspase assays. 59 In contrast, free anti-miR-21 LNA and CGKRK−pSiNPs loaded with a scrambled LNA did not result in any significant increase in caspase-3 activity relative to untreated cells ( Figure 2C). Treatment of OAW42 cells with anti-miR-21 CGKRK−pSiNPs led to a significant decrease in cell viability (∼50%), which demonstrated the potential efficacy of the anti-miR strategy in generating a therapeutic effect ( Figure 2D).…”

Sensitizing ovarian cancer cells to chemotherapy by interfering with pathways that are involved in the formation of cancer stem cells

“…Importantly, to simulate the clinical situation, where most tumor cells only receive only sub-toxic chemotherapy drug concentrations, [11][12][13] we used, in our subsequent in vitro studies, cisplatin concentrations that would not trigger killing of ovarian cancer cells in vitro and in vivo.…”

“…10 A series of studies demonstrated that intravenously injected chemotherapy drugs penetrate only a few cell layers from the blood vessel into the tumor. [11][12][13] This implies that more distant tumor cells are exposed to lower drug concentrations that are non-cytotoxic. It is thought that this triggers the formation of CSC that later drive cancer recurrence.…”

PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma

“…However the 5-year survival rate only reaches 18% [3]. The poor efficacy of the treatments results from the late diagnosis and from the limited and nonspecific access of chemotherapeutics to lung tumors after intravenous administration [4,5]. Pulmonary delivery is considered an attractive route of administration for chemotherapeutic agents, with the advantages of direct drug deposition at the diseased site and low systemic side effects.…”