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The development of safe and efficient delivery systems for targeted and controlled release of therapeutic agents has become a major focus in pharmacotherapy. The colon is one organ that serves as an optimal site for the absorption of protein and peptide drugs, offering significant potential for both localized and systemic therapies. However, effective drug delivery is challenged by the need to protect these drugs from premature absorption and maintain their stability across the varying pH levels of the gastrointestinal tract. In this study, we introduce, for the first time, a fully natural hydrogel system composed of N-acetylated chitosan and alginate, crosslinked using a phenylalanine-phenylalanine dipeptide. The hydrogel demonstrates a unique swelling behavior, allowing for a solvent-free drug-loading method and pH-sensitive release properties. In a colon-simulated pH environment, the hydrogel achieved a high drug release efficiency, with 77.6% of the tested drug sulfasalazine and 51% of hydrocortisone over 5 hours. These findings underscore hydrogel’s potential as a promising drug delivery carrier for targeted gastrointestinal treatments, with the capacity to enhance the efficacy of current therapeutic options.

As angiogenesis plays a pivotal role in tumor progression and metastasis, leading to more cancer-related deaths, the angiogenic process can be considered as a target for diagnostic and therapeutic applications. The vascular endothelial growth factor receptor-1 (VEGR-1) and VEGFR-2 have high expression on breast cancer cells and contribute to angiogenesis and tumor development. Thus, early diagnosis through VEGFR-1/2 detection is an excellent strategy that can significantly increase a patient’s chance of survival. In this study, the VEGFR1/2-targeting peptide VGB3 was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), using 6-aminohexanoic acid (Ahx) as a spacer to prevent steric hindrance in binding. DOTA-Ahx-VGB3 was radiolabeled with Gallium-68 (68Ga) efficiently. An in vitro cell binding assay was assessed in the 4T1 cell line. The tumor-targeting potential of [68Ga]Ga-DOTA-Ahx-VGB3 was conducted for 4T1 tumor-bearing mice. Consequently, high radiochemical purity [68Ga]Ga-DOTA-Ahx-VGB3 (RCP = 98%) was prepared and stabilized in different buffer systems. Approximately 17% of the radiopeptide was internalized after 2 h incubation and receptor binding as characterized by the IC50 value being about 867 nM. The biodistribution and PET/CT studies revealed that [68Ga]Ga-DOTA-Ahx-VGB3 reached the tumor site and was excreted rapidly by the renal system. These features convey [68Ga]Ga-DOTA-Ahx-VGB3 as a suitable agent for the noninvasive visualization of VEGFR-1/2 expression.