Enhanced Chemotherapy of Cancer Using pH-Sensitive Mesoporous Silica Nanoparticles to Antagonize P-Glycoprotein–Mediated Drug Resistance

Abstract

Multidrug resistance (MDR) is the major clinical obstacle in the management of cancer by chemotherapy. Overexpression of ATP-dependent efflux transporter P-glycoprotein (PGP) is a key factor contributing to multidrug resistance of cancer cells. The purpose of the present study was to use the endosomal pH-sensitive MSN (mesoporous silica nanoparticles; MSN-Hydrazone-Dox) for controlled release of doxorubicin (Dox) in an attempt to overcome the PGP-mediated MDR. In vitro cell culture studies indicate that uptake of MSNHydrazone-Dox by the human uterine sarcoma MES-SA/Dox-resistant tumor (MES-SA/Dx-5) cell occurs through endocytosis, thus bypassing the efflux pump resistance. This improves the efficacy of the drug and leads to significant cytotoxicity and DNA fragmentation evidenced by terminal deoxynucleotidyl transferasemediated dUTP nick end labeling and DNA laddering assays. In vivo studies show that the intratumor injection of MSN-Hydrazone-Dox induces significant apoptosis of MES-SA/Dox-resistant cancer cells. This is validated by active caspase-3 immunohistochemical analysis. However, MSN-Hydrazone, without doxorubicin conjugation, cannot induce apoptosis in vitro and in vivo. In conclusion, both in vitro and in vivo studies show that MSN could serve as an efficient nanocarrier entering cell avidly via endocytosis, thus bypassing the PGP efflux pump to compromise the PGP-mediated MDR. MSN-Hydrazone-Dox could further respond to endosomal acidic pH to release doxorubicin in a sustained manner. Besides the cell study, this is the first report that successfully shows the therapeutic efficacy of using MSN against MDR cancer in vivo. Mol Cancer Ther; 10(5); 761-9. Ó2011 AACR.

Mesoporous silica nanoparticles for stimuli-responsive controlled drug delivery: advances, challenges, and outlook

“…The pH-sensitive linkers, such as acetal bond, [65][66][67] hydrazine bond, [68][69][70][71] hydrazone bond, 72 and ester bond, 73,74 can be cleaved under acidic condition, thus providing opportunities for designing pH-responsive DDS applied in cancer treatment. Liu et al 65 reported a new pH-responsive nanocarrier by capping gold nanoparticles onto the surface of mesoporous silica through acid-labile acetal linkers ( Figure 3).…”

Nanoparticle delivery of anticancer drugs overcomes multidrug resistance in breast cancer

“…Nanoparticles that are taken up by the cell via endocytosis often bypass and evade the ABC-transporters responsible for efflux of cytotoxic drugs once released into the cytoplasm (Song et al, 2010;Huang et al, 2011;Cerqueira et al, 2015). There are four main mechanisms of endocytosis: clathrinmediated endocytosis, caveolae-mediated endocytosis, macropinocytosis, and other endocytosis.…”

“…Large amounts of drug delivered due to high pore volume and surface area (Qin et al, 2014) Surface modification easily accomplished (Hong et al, 2007) Use endocytic pathways to bypass active drug efflux (Lu et al, 2011) MSNs High drug-loading capacity due to large pore volume and surface area Uptake mainly by macropinocytosis clathrin mediated by folic acid receptors and caveolae-mediated mechanism ( Slowing et al, 2006;Huang et al, 2011;Shen et al, 2011) Inhibition of P-gp expression (Shen et al, 2011) DOI: 10.1080/10717544.2016 Pgp-, MRP1-, and MRP2-overexpressing membranes, Batrakova et al (2004) evaluated the effects of P85 on the kinetic parameters V max , K m and first-order rate constant (V max / K m ) of ATP hydrolysis by these ATPases. The effect of P85 on P-gp, MRP1 and MRP2 ATPase activity was as follows: MRP15MRP2 P-gp.…”

“…When DMNs were endocytosed into cells, doxorubicin would not be available for efflux by P-gp (Shen et al, 2011). Huang et al (2011) used the endosomal pH-sensitive MSN (MSN-Hydrazone-Dox) for controlled release of doxorubicin in cells while evading its P-gp-mediated efflux. Both in vitro and in vivo studies showed that MSNs could serve as an efficient nanodelivery system entering cell via endocytosis and thus bypassing P-gp mediated efflux.…”

Inorganic Nanocarriers Overcoming Multidrug Resistance for Cancer Theranostics

“…The drug‐loaded MSNs could enter cancer cells and transport the drugs into cytoplasm to finally kill MDR cancer cells, as the MSNs could protect the drugs inside their core to avoid the recognition by the MDR‐related efflux transporters, while the free drugs could be recognized by those drug efflux transporters to be pumped out of cancer cells, leading to therapeutic failure. Specifically, the Dox‐conjugated MSNs through endosomal pH‐cleavable bonds could deliver Dox into cellular plasma by endocytosis, while avoiding the recognition of efflux pump of resistant cancer cells, resulting in enhanced therapeutic efficacy with increased cellular apoptosis 131. Besides, it was recently reported that the Dox‐loaded MSNs exhibited pore‐size‐dependent and sustained drug release performance, while larger pore size resulted in faster drug release and higher intracellular drug levels to cause strong MDR‐reversing effects 132.…”