Abstract
The conventional targeted delivery of chemotherapeutic and diagnostic agents utilizing nanocarriers is a promising approach for cancer theranostics. Unfortunately, this approach often faces hindered tumor access that decreases the therapeutic index and limits the further clinical translation of a developing drug. Here, we demonstrated a strategy of simultaneously double-targeting the drug to two distinct cites of tumor tissue: the tumor endothelium and cell surface receptors. We used fourth-generation polyamideamine dendrimers modified with a chelated Gd and functionalized with selectin ligand and alpha-fetoprotein receptor-binding peptide. According to the proposed strategy, IELLQAR peptide promotes the conjugate recruitment to the tumor inflammatory microenvironment and enhances extravasation through the interaction of nanodevice with P- and E-selectins expressed by endothelial cells. The second target moiety—alpha-fetoprotein receptor-binding peptide—enhances drug internalization into cancer cells and the intratumoral retention of the conjugate. The final conjugate contained 18 chelated Gd ions per dendrimer, characterized with a 32 nm size and a negative surface charge of around 18 mV. In vitro contrasting properties were comparable with commercially available Gd-chelate: r1 relaxivity was 3.39 for Magnevist and 3.11 for conjugate; r2 relaxivity was 5.12 for Magnevist and 4.81 for conjugate. By utilizing this dual targeting strategy, we demonstrated the increment of intratumoral accumulation, and a remarkable enhancement of antitumor effect, resulting in high-level synergy compared to monotargeted conjugates. In summary, the proposed strategy utilizing tumor tissue double-targeting may contribute to an enhancement in drug and diagnostic accumulation in aggressive tumors.
Highlights
Cancer represents a complex disease type that causes substantial mortality in modern society
NPs possess a convenient structure for mono and multidrug loading, which allows for the construction of simple and complicated systems: multidrug-loaded NPs, theranostics, etc. [9–13]
The different location and expression levels of the selectins and AFP receptors at the same tumor nodes allowed us to improve targeted delivery on the nanovehicle compared to monotargeted conjugates
Summary
Cancer represents a complex disease type that causes substantial mortality in modern society. Nanoparticle (NP)-based drug delivery systems continue to attract enormous attention as important vehicles in cancer therapy [1] Due to their small size, variability of preparations and modifications, and specific tumor physiology, NPs are widely applied to enhance anticancer drug accumulation in tumor tissues and reduce side effects [2,3]. AFP and its receptor-binding fragments may provide a favorable drug distribution and high accumulation in tumor tissue, which makes their application attractive as vector molecules [29–31]. Multiple studies have demonstrated an enhanced antitumor effect of AFP or AFP-receptor binding fragments-decorated nanosystems in vitro and in vivo [32–34] Another widespread characteristic feature of tumor tissue is an inflammatory microenvironment. The different location and expression levels of the selectins (tumor endothelial cells) and AFP receptors (tumor cells) at the same tumor nodes allowed us to improve targeted delivery on the nanovehicle compared to monotargeted conjugates. We expect that the described study will provide information about the accumulation efficacy of this system in tumors, and help researchers choose the appropriate carrier, drug, or vector and evaluate the worthiness of the delivery approach that will be applied
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