期刊
ACS APPLIED MATERIALS & INTERFACES
卷 12, 期 46, 页码 51198-51211出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.0c13986
关键词
multidrug resistance; P-glycoprotein; acid-cleavable; polysaccharide nanoparticles; Lapatinib sensitization
资金
- National Natural Science Foundation of China [51973136, 51573113]
- Young Elite Scientists Sponsorship Program by CAST [2017QNRC001]
- Sichuan University Innovation Spark Project [2018SCUH0089]
For reversing the treatment failure in P-glycoprotein (P-gp)-associated MDR (multidrug resistance) of breast cancer, a high dose of Lapatinib (Lap), a substrate of breast cancer-resistant protein, was encapsulated into safe and effective acid-cleavable polysaccharide-doxorubicin (Dox) conjugates to form targeted HPP-Dox/Lap nanoparticles with an optimal drug ratio and appropriate nanosize decorated with oligomeric hyaluronic acid (HA) for specially targeting overexpressed CD44 receptors of MCF-7/ADR. The markedly increased cellular uptake and the strongest synergetic cytotoxicity revealed the enhanced reversal efficiency of HPP-Dox/Lap nanoparticles with reversal multiples at 29.83. This was also verified by the enhanced penetrating capacity in multicellular tumor spheroids. The reinforced Dox retention and substantial downregulation of P-gp expression implied the possible mechanism of MDR reversal. Furthermore, the efficient ex vivo accumulation and distribution of nanoparticles in the tumor site and the high tumor growth inhibition (93%) even at a lower dosage (1 mg/kg) as well as lung metastasis inhibition in vivo with negligible side effects revealed the overwhelming advantages of targeted polysaccharide nanoparticles and Lap-sensitizing effect against drug-resistant tumor. The development of an efficient and nontoxic-targeted polysaccharide delivery system for reversing MDR by synergistic therapy might provide a potential clinical application value.
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