Cancer Cell Membrane Decorated Silica Nanoparticle Loaded with miR495 and Doxorubicin to Overcome Drug Resistance for Effective Lung Cancer Therapy

Abstract

Current cancer therapy usually succumbs to many extracellular and intracellular barriers, among which untargeted distribution and multidrug resistance (MDR) are two important difficulties responsible for poor outcome of many drug delivery systems (DDS). Here, in our study, the dilemma was addressed by developing a cancer cell membrane (CCM)-coated silica (SLI) nanoparticles to co-deliver miR495 with doxorubicin (DOX) for effective therapy of lung cancer (CCM/SLI/R-D). The homologous CCM from MDR lung cancer cells (A549/DOX) was supposed to increase the tumor-homing property of the DDS to bypass the extracellular barriers. Moreover, the MDR of cancer cells were conquered through downregulation of P-glycoprotein (P-gp) expression using miR495. It was proved that miR495 could significantly decrease the expression of P-gp which elevated intracellular drug accumulation in A549/DOX. The in vitro and in vivo results exhibited that CCM/SLI/R-D showed a greatly enhanced therapeutic effect on A549/DOX, which was superior than applying miR495 or DOX alone. The preferable effect of CCM/SLI/R-D on conquering the MDR in lung cancer provides a novel alternative for effective chemotherapy of MDR cancers.

Nanoparticle-Based Drug Delivery in Cancer Therapy and Its Role in Overcoming Drug Resistance

“…Efflux transporters Bypass efflux transporters NP itself (Murakami et al, 2011) Inhibit efflux transporters COX-2 inhibitors (Zhang S. et al, 2019) P-gp-targeted siRNA (Patil et al, 2010;Navarro et al, 2012) miRNA-495 (He et al, 2019) Apoptosis Inhibit anti-apoptosis pathway Bcl-2-targeted siRNA (Wang et al, 2006;Saad et al, 2008;Chen et al, 2009;Choi et al, 2019) NF-κB inhibitors (pyrrolidine dithiocarbamate/curcumin) (Fan et al, 2010;Misra and Sahoo, 2011;Zhao et al, 2019) Activate pro-apoptosis pathway Ceramide (Devalapally et al, 2007;van Vlerken et al, 2010) p53 gene therapy (Prabha and Labhasetwar, 2004;Choi et al, 2008) Efflux transporters and apoptosis…”

“…Furthermore, several studies have revealed that co-delivery of P-gp-targeted siRNA and anticancer drugs by NPs helps overcome drug-resistant cancers, which is exerted through inhibiting the expression of ABC transporters ( Patil et al, 2010 ; Navarro et al, 2012 ). A recent study revealed the effectiveness of overcoming drug resistance in lung cancer therapy by combining miRNA-495 and doxorubicin into a cancer cell membrane-coated silica nanoparticle, results of which indicated that miR-495 effectively down-regulated P-gp expression in multidrug-resistant cancer cells ( He et al, 2019 ).…”

Nanoparticles for Cancer Therapy: Current Progress and Challenges

“…A recent study positively reflected upon reversing MDR in breast cancer cells by using NPs that co-deliver COX-2 inhibitors and doxorubicin [145]. Similarly, using silica NP that encapsulates miRNA-495 and doxorubicin has proved effective in overcoming drug resistance in lung cancer cells [146]. Another interesting study found out that using NPs in the tumor neovasculature targeting KDR receptors is more effective anti-tumor function than P-gp inhibitor combination therapy.…”

Bio-Nanocarriers for Lung Cancer Management: Befriending the Barriers

“… Approaches like multistage targeting that are difficult for conventional drug delivery systems have been employed using the nanocarriers [ 287 ] and may be combined with biotechnology to help devise the nano-biocarriers. Overcoming multidrug resistance with the possible use of P-gp inhibitors and nano-biocarriers [ 122 , 288 – 291 ]. Nano-biocarriers may facilitate ratiometric and synergistic drug delivery [ 292 ] or dosage form designing in a metronomic mode [ 293 ].…”

“…Overcoming multidrug resistance with the possible use of P-gp inhibitors and nano-biocarriers [ 122 , 288 – 291 ].…”