Synergetic Enhancement of Tumor Double-Targeted MRI Nano-Probe.

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.

• Authors: Nikita Yabbarov, Elena Nikolskaya, Maria Sokol, Mariia Mollaeva, Margarita Chirkina, Irina Seregina, Mikhail Gulyaev, Yury Pirogov, Rem Petrov
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 6 (Mar 14 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35328540 (Publication Type: Journal Article)

Chemical References

• Dendrimers
• alpha-Fetoproteins
• Gadolinium DTPA

Topics

• Cell Line, Tumor
• Dendrimers (chemistry)
• Endothelial Cells (pathology)
• Gadolinium DTPA
• Humans
• Magnetic Resonance Imaging (methods)
• Neoplasms (diagnostic imaging, drug therapy, pathology)
• Tumor Microenvironment
• alpha-Fetoproteins