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Abstract Intratumoral delivery and localized chemotherapy have demonstrated promise in tumor treatment; however, the rapid drainage of therapeutic agents from well-vascularized tumors limits their ability to achieve maximum therapeutic efficacy. Therefore, innovative approaches are needed to enhance treatment efficacy in such tumors. This study utilizes a mathematical modeling platform to assess the efficacy of combination therapy using anti-angiogenic drugs and drug-loaded nanoparticles. Anti-angiogenic drugs are included to reduce blood microvascular density and facilitate drug retention in the extracellular space. In addition, incorporating negatively charged nanoparticles aims to enhance diffusion and distribution of therapeutic agents within well-vascularized tumors. The findings indicate that, in the case of direct injection of free drugs, using compounds with lower drainage rates and higher diffusion coefficients is beneficial for achieving broader diffusion. Otherwise, drugs tend to accumulate primarily around the injection site. For instance, the drug doxorubicin, known for its rapid drainage, requires the prior direct injection of an anti-angiogenic drug with a high diffusion rate to reduce microvascular density and facilitate broader distribution, enhancing penetration depth by 200%. Moreover, the results demonstrate that negatively charged nanoparticles effectively disperse throughout the tissue due to their high diffusion coefficient. In addition, a faster drug release rate from nanoparticles further enhance treatment efficacy, achieving the necessary concentration for complete eradication of tumor compared to slower drug release rates. This study demonstrates the potential of utilizing negatively charged nanoparticles loaded with chemotherapy drugs exhibiting high release rates for localized chemotherapy through intratumoral injection in well-vascularized tumors.