Abstract：OBJECTIVE To prepare siRNA/HDL modified Dox/micelle multimeric polymer(siRNA/HDL-Dox/micelle) by using HDL as a siRNA carrier and a targeting ligand and to realize the effective co-delivery of siRNA and antitumor drug. METHODS HDL was incubated with chol-siRNA to prepare siRNA/LDL complex, then coupled with Dox/micelle to form siRNA/HDL modified Dox/micelle multimeric polymer (siRNA/HDL-Dox/micelle). The particle size and stability were investigated in different medium. HepG2/ADM with P-glycoprotein(P-gp) over-expressed were used to study the cell uptake, sub-cellular localization and anti-tumor efficacy in vitro. The ability of siRNA to silence target genes at mRNA and protein level was examined by RT-PCR and Western blot. RESULTS HDL exhibited an efficient binding ability for siRNA and protected siRNA from RNase. The size and surface morphology of siRNA/HDL-Dox/micelle confirmed by TEM showed that most of the micelles were compact and spherical, exhibited a narrow size distribution and good dispersion. The particle size and Zeta potential increased with increasing incubation time in pH 5.3 PBS. The siRNA was efficiently delivered into the cells by encapsulation into HDL, and the expression of P-gp is effectively down-regulated at the mRNA level and the protein level, thereby increasing the accumulation of intracellular Dox and enhancing the antitumor activity. CONCLUSION siRNA/HDL-Dox/micelle could effectively deliver siRNA and Dox into tumor cells, thereby exerting gene silencing, reversing tumor drug resistance and enhancing anti-tumor effect.
PATEL N R, PATTNI B S, ABOUZEID A H, et al. Nanopreparations to overcome multidrug resistance in cancer[J]. Adv Drug Deliv Rev, 2013,65(13-14):1748-1762.
[2]
ZHU W J, YANG S D, QU C X, et al. Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor[J]. Int J Nanomed, 2017, 12:3375-3393.
[3]
YANG S, WANG Y, REN Z, et al. Stepwise pH/reduction-responsive polymeric conjugates for enhanced drug delivery to tumor[J]. Mater Sci Eng C Mater Biol Appl, 2018, 82:234-243.
[4]
BALLARÍN-GONZÁLEZ B, HOWARD K A. Polycation-based nanoparticle delivery of RNAi therapeutics:adverse effects and solutions [J]. Adv Drug Deliv Rev, 2012, 64(15):1717-1729.
[5]
WANG L, SHI J, ZHANG H, et al. Synergistic anticancer effect of RNAi and photothermal therapy mediated by functionalized single-walled carbon nanotubes[J]. Biomaterials, 2013, 34(1):262-374.
[6]
AN S, KUANG Y, SHEN T, et al. Brain-targeting delivery for RNAi neuroprotection against cerebral ischemia reperfusion injury[J]. Biomaterials, 2013, 34(35):8949-8959.
[7]
YANG S D, ZHU W J, ZHU Q L, et al. Binary-copolymer system base on low-density lipoprotein-coupled N-succinyl chitosan lipoic acid micelles for co-delivery MDR1 siRNA and paclitaxel, enhances antitumor effects via reducing drug[J]. J Biomed Mater Res B Appl Biomater, 2017, 105(5):1114-1125.
[8]
ZHANG C G, YANG S D, ZHU W J, et al. Distinctive polymer micelle designed for siRNA delivery and reversal of MDR1 gene-dependent multidrug resistance[J]. J Biomed Mater Res B Appl Biomater, 2017, 105(7):2093-2106.
[9]
ZHU Q L, ZHOU Y, GUAN M, et al. Low-density lipoprotein-coupled N-succinyl chitosan nanoparticles co-delivering siRNA and doxorubicin for hepatocyte-targeted therapy[J]. Biomaterials, 2014, 35(22):5965-5976.
[10]
LUO H, WANG X, ZHANG R, et al. Patient-specific therapy via cell-reprogramming technology:a curative potential for patients with diabetes[J]. Nanoscale Res Lett, 2015, 10(1):496.
[11]
WU Y F, WU H C, KUAN C H, et al. Multi-functionalized carbon dots as theranostic nanoagent for gene delivery in lung cancer therapy[J]. Sci Rep, 2016, 6:21170.
[12]
THAXTON C, RINK J S, NAHA P C, et al. Lipoproteins and lipoprotein mimetics for imaging and drug delivery[J]. Adv Drug Deliv Rev, 2016, 106(Pt A):116-131.
[13]
JIANG W, LIU B R, YANG M. Research progress of high-density lipoprotein as an antitumor drug carrier in cancer[J]. Mod Oncol (现代肿瘤医学), 2014,22(10):2473-2476.
[14]
LIU C, LI S N, WANG Y, et al. Advances in research of high density lipoprotein and low density lipoprotein nano-complexes as anti-cancer drug targeting carriers[J]. Chin New Drugs J(中国新药杂志), 2017,26(3):285-289
[15]
KUAI R, LI D, CHEN Y E, et al. High-density lipoproteins (HDL)-nature's multi-functional nanoparticles[J]. ACS Nano, 2016, 10(3):3015-3041.
[16]
MOOBERRY L K, SABNIS N A, PANCHOO M, et al. Targeting the SR-B1 receptor as a gateway for cancer therapy and imaging[J]. Front Pharmacol, 2016, 7:466.
[17]
MCMAHON K M, THAXTON C S. High density lipoproteins for the systemic delivery of short interfering RNA[J]. Expert Opin Drug Deliv, 2014, 11(2):231-247.
[18]
ZHANG C G, ZHU W J, LIU Y, et al. Novel polymer micelle mediated co-delivery of doxorubicin and P-glycoprotein siRNA for reversal of multidrug resistance and synergistic tumor therapy[J]. Sci Rep, 2016, 6:23859.
[19]
CHENG R, MENG F, DENG C, et al. Bioresponsive polymeric nanotherapeutics for targeted cancer chemotherapy[J]. Nano Today, 2015, 10(5):656-670.
2020, Vol. 55 
