Over the past decade, there has been increasing interest in the use of multifunctional nanoparticles (NPs) for cancer treatment. Of importance are systems that can deliver drugs at a sustained rate to target cancer cells, which can result in higher efficiency and reduced systemic toxicity. In this study, we present the route for the synthesis of tantalum pentoxide (Ta2O5) NPs with a particle size of 27 nm that were individually coated with poly(acrylic acid) (PAA) with a different layer thickness of 2–8 nm by in-situ polymerization of the acrylic acid monomer. The capability of Ta2O5-PAA to provide anatomical contrast-enhancing features has been demonstrated via computed tomography. The Ta2O5-PAA conjugate was further loaded with methotrexate, and the drug release was observed for a total of 72 h at a pH of 3.6, 5.4, 7.4, and 9.4. While the different layer thicknesses did not influence the drug release kinetics, a decrease in pH of the release medium resulted in a slower drug release. The developed nanocomposite particles present a great potential as a theranostic system for biomedical applications.