Sequential targeted delivery of paclitaxel and camptothecin using a cross-linked "nanosponge" network for lung cancer chemotherapy.
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.
Department of Chemistry, Vanderbilt University , 7618 Stevenson Center, Nashville, Tennessee 37235-1822, United States.
Ghazal
G
Hariri
Aaron D
AD
Edwards
Tyler B
TB
Merrill
Joshua M
JM
Greenbaum
Alice E
AE
van der Ende
Eva
E
Harth
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000008:administration & dosage; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage; D010446:Peptide Fragments / Q000737:chemistry*; D011839:Radiation, Ionizing; D014407:Tumor Cells, Cultured
D003432:Cross-Linking Reagents; D004337:Drug Carriers; D010446:Peptide Fragments; D017239:Paclitaxel; D002166:Camptothecin