Sequential Targeted Delivery of Paclitaxel and Camptothecin Using a Cross-Linked “Nanosponge” Network for Lung Cancer Chemotherapy

Abstract

The applicability of a HVGGSSV peptide targeted "nanosponge" drug delivery system for sequential administration of a microtubule inhibitor (paclitaxel) and topoisomerase I inhibitor (camptothecin) was investigated in a lung cancer model. Schedule-dependent combination treatment with nanoparticle paclitaxel (NP PTX) and camptothecin (NP CPT) was studied in vitro using flow cytometry and confocal imaging to analyze changes in cell cycle, microtubule morphology, apoptosis, and cell proliferation. Results showed significant G2/M phase cell cycle arrest, changes in microtubule dynamics that produced increased apoptotic cell death and decreased proliferation with initial exposure to NP PTX, followed by NP CPT in lung cancer cells. In vivo molecular imaging and TEM studies validated HVGGSSV-NP tumor binding at 24 h and confirmed the presence of Nanogold labeled HVGGSSV-NPs in tumor microvascular endothelial cells. Therapeutic efficacy studies conducted with sequential HVGGSSV targeted NP PTX and NP CPT showed 2-fold greater tumor growth delay in combination versus monotherapy treated groups, and 4-fold greater delay compared to untargeted and systemic drug controls. Analytical HPLC/MS methods were used to quantify drug content in tumor tissues at various time points, with significant paclitaxel and camptothecin levels in tumors 2 days postinjection and continued presence of both drugs up to 23 days postinjection. The efficacy of the NP delivery system in sequential treatments was corroborated in both in vitro and in vivo lung cancer models showing increased G2/M phase arrest and microtubule disruption, resulting in enhanced apoptotic cell death, decreased cell proliferation and vascular density.

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“…[8][9][10][11] SCNP technology is advantageous in these areas due in large part to the small size of the nanoparticles and the ease in which they can be tailored to specific uses. [8][9][10][11] SCNP technology is advantageous in these areas due in large part to the small size of the nanoparticles and the ease in which they can be tailored to specific uses.…”

“…Advances in this technology will have applications in catalysis, [1][2][3][4][5] sensors, 6 nanoreactors, 7 nanomedicine, [8][9][10][11] etc. In this light, an obvious yet unmet research goal becomes apparent: exploiting our understanding of biomolecules to mimic this behavior in the laboratory using recent advances in controlled polymerization chemistry and the well-known theories of modern polymer physics.…”

Organic nanoparticle systems for spatiotemporal control of multimodal chemotherapy

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