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J Thorac Cardiovasc Surg 2008;135:1014-1021
© 2008 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Prevention of local tumor growth with paclitaxel-loaded microspheres

Solomon M. Azouz, MSa, Joseph Walpole, BSa, Sepideh Amirifeli, MDa, Kendra N. Taylor, PhDa, Mark W. Grinstaff, PhDb, Yolonda L. Colson, MD, PhDa,*

a Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Mass
b Departments of Biomedical Engineering and Chemistry, Boston University, Boston, Mass

Received for publication October 24, 2007; revisions received December 18, 2007; accepted for publication December 22, 2007.

* Address for reprints: Yolonda L. Colson, MD, PhD, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. (Email: ycolson{at}partners.org).

Objectives: Lung cancer is associated with a significant rate of locoregional recurrence after surgical resection, particularly when nonanatomic wedge resections are performed. The primary aim of this study was to assess the feasibility of a microsphere drug delivery system to locally deliver chemotherapy and prevent the establishment and growth of lung cancer cells and establish proof of concept for a potential future approach to target occult microscopic disease remaining at the surgical resection margin.

Methods: Poly-(D,L-lactic-co-glycolic acid) (PLGA) microspheres loaded with the antineoplastic agent paclitaxel were prepared and tested for antitumor efficacy in an in vitro cell proliferation assay for tumor inhibition and induction of apoptosis. The in vivo prevention of Lewis lung carcinoma cell establishment and growth in subcutaneous tissues of mice was also assessed by comparing 4 treatment groups: Lewis lung carcinoma cells alone, Lewis lung carcinoma cells combined with 100 x 106 unloaded (carrier alone) PLGA microspheres, and Lewis lung carcinoma cells combined with 50 x 106 or 100 x 106 paclitaxel-loaded PLGA microspheres. After the coinjection of Lewis lung carcinoma cells with or without microspheres, in vivo tumor growth was monitored, and tumor weight was recorded on death.

Results: Paclitaxel-loaded PLGA microspheres were found to effectively prevent growth of tumor cells in culture through the induction of apoptosis. Similarly, paclitaxel-loaded PLGA microspheres significantly inhibited tumor growth in vivo at both the 50 x 106 and 100 x 106 microsphere dose (0.497 ± 0.183 and 0.187 ± 0.083 g total tumor weight, respectively) compared with 2.91 ± 0.411 g for Lewis lung carcinoma cells with unloaded microspheres and 3.37 ± 0.433 g for untreated tumor (P < .001). Toxicity was not clinically apparent in any animal treated with paclitaxel-loaded PLGA microspheres.

Conclusions: Paclitaxel-loaded PLGA microspheres induce tumor apoptosis and inhibit the establishment and growth of lung cancer cells both in vitro and in vivo without obvious systemic toxicity. By using models consistent with localized microscopic tumor burdens, these results suggest that local delivery of paclitaxel through a microsphere system might lead to an effective future method of decreasing local tumor recurrence in non–small cell lung cancer when applied to the surgical margins at risk for microscopic tumor foci. Such an approach might be particularly efficacious after wedge resection in the setting of poor pulmonary reserve or significant comorbidity, where local recurrence rates are increased and acceptable alternative treatment options are limited.

Abbreviations and Acronyms BSA = bovine serum albumin; DMEM = Dulbecco's modified Eagle's medium; DMSO = dimethyl sulfoxide; ELISA = enzyme-linked immunosorbent assay; FBS = fetal bovine serum; IC50 = amount of paclitaxel necessary to inhibit the growth of lung cancer tumor cells by 50%; LLC = Lewis lung carcinoma cell; MTT = 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide; Pax-PLGA = paclitaxel-loaded poly-(D,L-lactic-co-glycolic acid); PI = propidium iodide; SEM = scanning electron microscopy






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