Abstract
Current chemotherapy treatments are limited by poor drug solubility, rapid drug clearance and systemic side effects. Additionally, drug penetration into solid tumors is limited by physical diffusion barriers [e.g., extracellular matrix (ECM)]. Nanoparticle (NP) blood circulation half-life, biodistribution and ability to cross extracellular and cellular barriers will be dictated by NP composition, size, shape and surface functionality. Here, we investigated the effect of surface charge of poly(lactide)-poly(ethylene glycol) NPs on mediating cellular interaction. Polymeric NPs of equal sizes were used that had two different surface functionalities: negatively charged carboxyl (COOH) and neutral charged methoxy (OCH(3)). Cellular uptake studies showed significantly higher uptake in human brain cancer cells compared to noncancerous human brain cells, and negatively charged COOH NPs were uptaken more than neutral OCH(3) NPs in 2D culture. NPs were also able to load and control the release of paclitaxel (PTX) over 19 days. Toxicity studies in U-87 glioblastoma cells showed that PTX-loaded NPs were effective drug delivery vehicles. Effect of surface charge on NP interaction with the ECM was investigated using collagen in a 3D cellular uptake model, as collagen content varies with the type of cancer and the stage of the disease compared to normal tissues. Results demonstrated that NPs can effectively diffuse across an ECM barrier and into cells, but NP mobility is dictated by surface charge. In vivo biodistribution of OCH(3) NPs in intracranial tumor xenografts showed that NPs more easily accumulated in tumors with less collagen. These results indicate that a robust understanding of NP interaction with various tumor environments can lead to more effective patient-tailored therapies.