Biomimetic Nanocarriers for Enhanced Drug Diffusion in Prostate Tumors with a High Level Hyaluronan

Cancer therapies aim to eliminate malignant tumor tissues that grow uncontrollably within patients. However, due to many challenges unique cancer microenvironments pose; chemotherapeutic agents have low accumulation and diffusion through the tumor tissues. Pharmacokinetics and toxicity of these therapeutic agents can be altered with engineered biomimetic nanocarriers for targeted drug delivery applications to increase the efficacy and reduce the side effects of drugs. The motivation of this project is to develop a biomimetic nanocarrier to increase drug accumulation and diffusion in tumors with high levels of hyaluronan (HA). We envision that red blood cell (RBC) membrane coated poly(lactic-co-glycolic acid) (PLGA) nanocarriers with extra cellular matrix degrading enzymes (ECMDEs) on surfaces are ideal candidates for this purpose because this platform combines the advantages of various biomimetic platforms. PLGA core supports the RBC vesicle and allows sustained drug release, while the RBC vesicle provides natural camouflage within the body extending circulation time. RBC membrane surface also allows the attachment of ECMDEs to degrade tumor ECM that poses a challenge for drug distribution. For the first time RBC-PLGA nanocarriers with hyaluronidase (HAase) as the ECMDE on surfaces were successfully created. These RBC-PLGA-NPs with HAase on surfaces were shown to facilitate NP diffusion through a pericellular HA layer around prostate cancer cell line PC3, illustrating the potential of this nanocarriers for enhanced drug diffusion within tumors with high levels of HA.