Integration of phospholipid-hyaluronic acid-methotrexate nanocarrier assembly and amphiphilic drug-drug conjugate for synergistic targeted delivery and combinational tumor therapy.

Abstract

Combinational cancer therapy has been considered as a promising strategy to achieve synergetic therapeutic effects and suppression of multidrug resistance. Herein, we adopted a combination of methotrexate (MTX), an antimetabolite acting on cytoplasm, and 10-hydroxycamptothecin (HCPT), an alkaloid acting on nuclei, to treat cancer. Given the different solubilities, membrane permeabilities, and anticancer mechanisms of both drugs, we developed a dual-targeting delivery system based on 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-hyaluronic acid (a principal ligand of CD44 receptors)-MTX (a selective ligand of folate receptors) nanoparticles, which was exploited to carry HCPT-MTX conjugate for synergistically boosting dual-drug co-delivery. The HCPT-MTX conjugate was synthesized by a blood-stable yet intracellularly hydrolysable ester bond. The core-shell-corona DSPE-HA-MTX nanoparticles encapsulating HCPT-MTX (HCPT-MTX@DHM) exhibited high drug entrapment efficiency (∼91.8%) and pH/esterase-controlled release behavior. Cellular uptake studies confirmed significant increase in the efficiency of selective internalization of HCPT-MTX@DHM via CD44/folate receptors compared with those of DSPE-HA nanoparticles encapsulating HCPT-MTX (HCPT-MTX@DH), both drugs, or each individual drug. Furthermore, in vivo near-infrared fluorescence and photoacoustic dual-modal imaging indicated that DiR-doped HCPT-MTX@DHM nanoparticles efficiently accumulated at the tumor sites through passive-plus-active targeting. Finally, the synergistic active targeting and synchronous dual-drug release at a synergistic drug-to-drug ratio resulted in highly synergetic tumor cell-killing and tumor growth inhibition in MCF-7 tumor-bearing mice. Therefore, HCPT-MTX@DHM nanoparticles can be an efficient and smart platform for tumor-targeting therapy.

• Authors: Yang Li , Huabing Zhang , Yilin Chen , Jinyuan Ma , Jinyan Lin , Yinying Zhang , Zhongxiong Fan , Guanghao Su , Liya Xie , Xuan Zhu , Zhenqing Hou
• Journal: Biomaterials science (Biomater Sci) Vol. 6 Issue 7 Pg. 1818-1833 (Jun 25 2018) ISSN: 2047-4849 [Electronic] England
• PMID: 29785434 (Publication Type: Journal Article)

Chemical References

• Antimetabolites, Antineoplastic
• Antineoplastic Agents, Phytogenic
• Drug Carriers
• Folate Receptors, GPI-Anchored
• Phosphatidylethanolamines
• Hyaluronic Acid
• Folic Acid
• 10-hydroxycamptothecin
• Camptothecin
• Methotrexate

Topics

• Adenocarcinoma (drug therapy, metabolism, mortality, pathology)
• Animals
• Antimetabolites, Antineoplastic (chemistry, pharmacology)
• Antineoplastic Agents, Phytogenic (chemistry, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Breast Neoplasms (drug therapy, metabolism, mortality, pathology)
• Camptothecin (analogs & derivatives, chemistry, pharmacology)
• Drug Carriers
• Drug Compounding (methods)
• Drug Synergism
• Female
• Folate Receptors, GPI-Anchored (genetics, metabolism)
• Folic Acid (metabolism)
• Humans
• Hyaluronic Acid (chemistry)
• MCF-7 Cells
• Methotrexate (chemistry, pharmacology)
• Mice
• Mice, Nude
• Nanoparticles (administration & dosage, chemistry, metabolism)
• Phosphatidylethanolamines (chemistry)
• Survival Analysis
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays