Prevention Of Local Tumor Growth With Paclitaxel Loaded Microspheres
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Objective:
Lung Cancer is the leading cause of cancer deaths in both men and women. Surgical resection offers the best chance of cure for patients with localized disease, however, local recurrence occurs in 9-16% of patients. Our objective is to prevent local recurrence by delivering anti-neoplastic agents to the surgical resection margin without impairing healing. To this aim, we have manufactured and characterized poly-D,L lactic-co-glycolic acid (PLGA) microspheres loaded with paclitaxel (Pax) to locally deliver this chemotherapeutic agent to inhibit malignant cell growth invitro and invivo.
Methods:
To rule out non-specific toxicity and document dose-dependent anti-neoplastic activity, increasing concentrations of control (DMSO loaded) or 1-10um PLGA-Pax spheres were co-incubated with 3000 tumor cells from murine Melanoma B16, murine Lewis Lung Carcinoma (LLC) or Calu 6 human lung carcinoma lines in vitro. Tumor growth was assessed after 3,5, and 7 days of coculture with spheres. To determine anti-tumor potential of PLGA-Pax spheres in vivo, these spheres were tested in a well-established animal tumor model whereby subcutaneous injection of 75 x 105 LLC tumor cells in C57Bl/6 mice results in tumor nodules within 1 week and rapid growth requiring sacrifice within 2-3 weeks.
Results:
PLGA-Pax spheres completely inhibited tumor growth in vitro at ratios of 4-8 spheres/tumor cell for all lines. Tumor cell death increased with longer co-incubation times, an effect not noted with direct Pax exposure, suggesting that prolonged drug release may allow lower Pax concentrations to be effectively utilized by this delivery method. 10 x 106 PLGA-Pax spheres co-injected with tumor cells subcutaneously demonstrated effective anti-neoplastic activity, without toxicity, in vivo with significantly decreased tumor size in animals receiving LLC cells and PLGA-Pax spheres vs. LLC cells alone (1.0 ± 1.4g vs. 3.8 ± 0.9g, p<0.05, figure). Over 70% of PLGA-Pax treated animals developed minimal to no evidence of tumor implantation during the study.
Conclusions:
Local delivery of Pax via microspheres deterred the growth and subcutaneous establishment of lung carcinoma in these in vivo and in vitro models, suggesting that PLGA-Pax spheres may be clinically applicable to patients able to tolerate only limited pulmonary resection. These results form the basis to incorporate PLGA-Pax spheres within the surgical resection margin as a means to prevent local tumor recurrence, with focused assessment of both effectiveness and local tissue toxicity. 
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