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| Size- and Polymer-Dependent Intranodal Localization of Methacrylate Nanoparticles |
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Onkar Khullar1, Kimberly Ann V. Zubris2, Aaron P. Griset2, John V. Frangioni3, Mark W. Grinstaff2, Yolonda L. Colson1; 1 Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 2 Departments of Biomedical Engineering and Chemistry, Boston University, Boston, MA; 3 Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA Objective: Despite improvements in current therapy, the presence of nodal disease decreases 5-year survival in NSCLC by 40%. A simple method to concentrate toxic chemotherapy within these lymph nodes (LNs) could substantially improve survival in patients with NSCLC. This study investigates various formulations of acrylate-based nanoparticles (NP) as a method for locoregional lymphatic drug delivery, targeting these LNs at risk. Methods: Two distinct NP formulations were synthesized from acrylate monomers with either a trimethoxybenzaldehyde or 12 carbon (C12) side-chain. In order to study to the effects of particle size on migration each formulation was synthesized in two sizes (50-60 nm and >100 nm). A 400 µL suspension of each NP, fluorescently labeled with coumarin and encapsulating the near infrared (NIR) dye IR-786, was injected subcutaneously into the chest wall or hindleg of pigs. Animals were imaged 24 hours post-injection using the FLARE™ NIR imaging system to assess for lymphatic migration. Fluorescent LNs containing NP were excised, cryosectioned, and examined for the presence of coumarin-labeled NPs and IR-786 payload with fluorescent microscopy. Results: Successful migration of NPs from injection site to the sentinel lymph node (SLN) was size-dependent. 50 nm and 60 nm NP showed migration to the regional SLN(s) within 24 hours of injection in all cases (n = 6 for each polymer; Figure 1), while particles 100 nm or larger, irrespective of polymer side chain, showed minimal migration in only 1 instance (n = 4 for each polymer; p < 0.01, Fisher’s Exact Test). Additionally, the pattern of migration varied depending on the NP polymer. Histologic examination of the SLN confirmed that varying the side chains of the acrylate monomer resulted in localization within different compartments of the LN. 50 nm particles with a trimethoxybenzaldehyde side chain remained confined within the subcapsular and sinusoidal spaces of the LN, while similarly sized particles with C12 side chain localized to the germinal centers. Conclusion: This study demonstrates the capabilities of polymer NP for drug delivery to various lymphatic targets. Migration characteristics of NP were both size and polymer dependent. By adjusting particle diameter and formulation, NP can be targeted to various compartments within a LN including the subcapsular spaces and germinal centers. Given the differing LN functions in these areas, these targeting methods may prove useful for future oncologic and immunologic lymphatic therapies.  Figure 1: NIR-labeled 60 nm methacrylate nanoparticles with a C12 side chain migrate from the subcutaneous injection site (arrowhead) to the regional draining lymph nodes (arrow) through a faint lymphatic channel (open arrow). Back to 2010 Annual Meeting Back to Program Outline Back to Main Program |
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