We have developed doxorubicin (DOX)-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (DP) conjugated with polyethylene glycol (PEG) and transferrin (Tf) to form Tf-PEG-DPs (TPDPs), and incorporated these TPDPs into three-dimensional (3-D) PLGA porous scaffolds to form a controlled delivery system. To our knowledge, this represents the first use of a Tf variant (oxalate Tf) to improve the targeted delivery of drug-encapsulated nanoparticles (NPs) in PLGA scaffolds to PC3 prostate cancer cells. The PLGA scaffolds with TPDPs incorporated have been shown to release drugs for sustained delivery and provided a continuous release of DOX. The MTS assay was also performed to determine the potency of native and oxalate TPDPs, and a 3.0-fold decrease in IC50 values were observed between the native and oxalate TPDPs. The lower IC50 value for the oxalate version signifies greater potency compared to the native version, since a lower concentration of drug was required to achieve the same therapeutic effect. These results suggest that this technology has potential to become a new implantable polymeric device to improve the controlled and targeted drug delivery of Tf-conjugated NPs for cancer therapy.