This paper focused on the biodistribution of the cross-linked hyaluronic acid (HA-NPs) sub-micron particles in tumor-bearing mice. Solvent-non solvent method followed glutaraldehyde cross-linking utilized for the fabrication of HA-NPs. Size measurement and morphological analysis were performed by dynamic light scattering and electron microscopy, respectively and the size found to be in the range of 200-400 nm. In vitro viability in LNCaP cell line was assessed by water soluble tetrazolium assay after 24 h of exposure to sub-micron particles and no toxicity was found to higher concentration of 3 mg/mL. Internalization of particles in prostate cancer cell LNCaP were studied by confocal microscopy with FITC labeled submicron particles and involvement of hyaluronan receptor mediated uptake/endocytosis was confirmed by competitive assay. Biodistribution studies were performed in xenograft prostate cancer mice model with fluorophore labeled particles and monitored in tumoral parenchyma with strong fluorescence, meanwhile very less signal in liver, kidney and spleen while no fluorescence found in lung after 24 h of systemic administration; that shown ability of this HA based system to recognize cancer tissue. These result fetched that hyaluronic acid based system is selective for tumoral site and can be utilized to deliver bioactives in specific (targeting) and controlled (temporal) manner to cancerous tissue.