Abstract 3110: Optimizing nanoparticle surface properties using SPR for improved therapeutic efficacy against triple-negative breast cancer tumors
Authors: Dancy Jimena G. , Wadajkar Aniket S. , Woodworth Graeme F. , Winkles Jeffrey A. , Kim Anthony J. 
Published: July 2017

Many of the nanoparticle (NP) formulations approved for clinical use in solid tumor therapy provide only modest improvements in patient survival. This is in part due to NP tumor penetration barriers, including a dense and complex extracellular matrix (ECM) and an elevated interstitial fluid pressure, which hinder the penetration of drugs and NPs into and within tumors limiting therapeutic efficacy. Using polystyrene (PS) particles over the size range of 20-100 nm, we recently tested how particle size impacted NP diffusion in a well-characterized tumor ECM preparation (Matrigel) and in triple-negative MDA-MB-231 breast cancer xenografts by multiple particle tracking (MPT) and intravital microscopy. We also investigated the effect of PEG surface density on the diffusion of ~60 nm PS NPs in the same models. Nonspecific binding of the NPs to tumor ECM components was determined by a surface plasmon resonance (SPR) binding assay, which was then compared to the NP diffusion results. Furthermore, biodegradable PLGA NPs with various surface PEG densities and two clinically-relevant NPs, PEGylated liposomal doxorubicin (Doxil) and non-PEGylated albumin-bound paclitaxel (Abraxane), were evaluated by SPR to evaluate their potential tumor penetration ability. These studies demonstrated that NPs as large as 60 nm, but less than 110 nm in diameter, diffuse rapidly within tumor ECM and tumor xenograft tissues ex vivo if they are densely coated with PEG. The penetration of these NPs within the same tumor models was found to be highly dependent on surface PEG density. Intravital microscopy of NP spread in living tissue confirmed a significant difference in tumor tissue penetration between the 60 and 110 nm PEG-PS NPs, as well as between PEG-coated and uncoated NPs. Non-specific binding of NPs to tumor ECM components was assessed by SPR, which revealed a positive correlation with the particle diffusion results consistent across multiple particle types, including PS and biodegradable NPs. SPR assays revealed that Abraxane binds significantly to tumor ECM which has the potential to limit particle dispersion with tumor tissue. Studies to extend these findings to drug-loaded, molecularly-targeted biodegradable NPs are underway. We have successfully encapsulated paclitaxel to the polymer backbone of PLGA containing a low-molecular weight PEG coating. Additional surface modifications have been made to enable NP targeting to Fn14-positive triple-negative breast tumors. In summary, we have developed a NP platform that can diffuse and penetrate within tumor tissue and selectively target tumors. Using this approach, we can optimize therapeutics versions to improve drug efficacy while limiting many of the side effects and risks of free drug and non-targeted therapies.

Citation Format: Jimena G. Dancy, Aniket S. Wadajkar, Graeme F. Woodworth, Jeffrey A. Winkles, Anthony J. Kim. Optimizing nanoparticle surface properties using SPR for improved therapeutic efficacy against triple-negative breast cancer tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3110. doi:10.1158/1538-7445.AM2017-3110