The Anti-tumor Nano-drug Carrier System Modified by the Nuclear Localization Signal Peptide
LI Ruo-Jin1), WU Xiao-Xue1), WANG Che1),2)*
1)College of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, Liaoning, China; 2)Liaoning Key Laboratory of Biotechnology and Molecular Drug Development, Dalian 116081, Liaoning, China
Abstract:Nano-drug carrier systems, as the controllable and targeting tool to deliver drugs, can effectively improve the drug bioavailability, enhance their therapeutic outcomes and reduce side effects, mainly through protecting drugs from rapid enzymatic degradation and blood clearance and ensuring them to be delivered to the targeting sites. The nano-drug carrier system owns broad application prospects in the biomedical field and attracts increasing attention in both functional materials and anti-tumor research. Recently, functional surface modification with functional biomolecules to improve the biocompatibility and drug bioactivity is a hot topic in nano medicine research. The nucleus is the main site of action for many anti-tumor substances. And nuclear localization signal (NLS) peptides, as a type of functional peptides with nuclear-targeting activity, can penetrate through biological membranes and target the nucleus and is considered to be a universal tool for constructing nano-drug carrier systems. The use of NLS peptides to construct a functionalized nano-drug carrier system with nuclear targeting ability has important application values in the field of anti-tumor therapy. Although the synthesis process of nuclear-targeted functionalized nano-drug carrier system has been developed, due to the high preparation cost and complex synthesis process, there is still a long research process in the successful translation of nuclear-targeted nanocarriers from the experimental stage to the clinical stage. This review mainly focuses on the composition and construction of the nuclear-targeted functionalized nano-drug carrier system, analyzes its nuclear entry methods and conditions, and prospects the development of the anti-tumor nano-drug carrier system in the future based on the current challenges.
李若瑾, 吴晓雪, 王澈. 核定位信号肽修饰的抗肿瘤纳米载药体系[J]. 中国生物化学与分子生物学报, 2022, 38(1): 35-41.
LI Ruo-Jin, WU Xiao-Xue, WANG Che. The Anti-tumor Nano-drug Carrier System Modified by the Nuclear Localization Signal Peptide. Chinese Journal of Biochemistry and Molecular Biol, 2022, 38(1): 35-41.
[1] DeLong RK, Cheng YH, Pearson P, et al.Translating nanomedicine to comparative oncology—the case for combining Zinc oxide nanomaterials with nucleic acid therapeutic and protein delivery for treating metastatic cancer[J]. Pharmacol Exp Ther, 2019, 370: 671-681 [2] Pan LM, Liu JN, Shi JL. Cancer cell nucleus-targeting nanocomposites for advanced tumor therapeutics [J].Chem Soc Rev,2018,47(18): 6930-6946 [3] Hu B, Zhong LP, Weng Yh, et al. Therapeutic siRNA:state of the art[J]. Signal Transduct Target Ther, 2020, 5(1): 101 [4] Pan JB, Wang YQ, Pan HY, et al. Mimicking drug-substrate interaction: A smart bioinspired technology for the fabrication of theranostic nanoprobes [J]. Adv Funct Mater, 2017, 27: 8-19 [5] Kim YJ, Perumalsamy H, Castro-Aceituno V, et al. Photoluminescent and self-assembled hyaluronic acid-zinc oxide-ginsenoside Rh2 nanoparticles and their potential caspase-9 apoptotic mechanism towards cancer cell lines[J]. Int J Nanomedicine, 2019, 14: 8195-8208 [6] Marcelo GA, Lodeiro C, Capelo JL, et al.Magnetic, fluorescent and hybrid nanoparticles: From synthesis to application in biosystems[J].Mater Sci Eng C Mater Biol Appl, 2020, 106: 110104 [7] Han HS, Choi KY, Ko H, et al. Bioreducible core-crosslinked hyaluronic acid micelle for targeted cancer therapy [J].J Control Release, 2015, 200: 158-166 [8] Prasetyanto EA, Bertucci A, Septiadi D, et al. Breakable hybrid organosilica nanocapsules for protein Delivery[J]. Angew Chem Int Ed Engl, 2016, 55(10): 3323-3327 [9] Li ZL, Zhang H, Han J, et al. Surface Nanopore Engineering of 2D MXenes for Targeted and Synergistic Multitherapies of Hepatocellular Carcinoma [J]. Adv Mat, 2018, 30(25): e1706981 [10] Lange A, Mills RE, Lange CJ, et al. Classical nuclear localization signals: definition, function, and interaction with importin alpha [J]. J Biol Chem, 2007, 282(8): 5101-5105 [11] Hayashi R, Takeuchi N, Ueda T. Nuclear respiratory factor 2β (NRF-2β) recruits NRF-2α to the nucleus by binding to importin-α:β via an unusual monopartite-type nuclear localization signal[J]. J Mol Biol, 2013, 425(18): 3536-3548 [12] DeVit MJ, Johnston M. The nuclear exportin Msn5 is required for nuclear export of the Mig1 glucose repressor of Saccharomyces cerevisiae [J]. Curr Biol, 1999, 9(21): 1231-1241 [13] Fahrenkrog B, Aebi U.The vertebrate nuclear pore complex: from structure to function [J]. Results Probl Cell Differ, 2002, 35: 25-48 [14] Fahrenkrog B, Aebi U. The nuclear pore complex: nucleocytoplasmic transport and beyond [J].Nat Rev Mol Cell Biol, 2003, 4(10): 757-766 [15] Fanara P, Hodel MR, Corbett AH, et al. Quantitative analysis of nuclear localization signal (NLS)-importin alpha interaction through fluorescence depolarization. Evidence for auto-inhibitory regulation of NLS binding [J]. J Biol Chem, 2000, 275(28): 21218-21223 [16] Rong J, Li PC, Ge YK, et al. Histone H2A-peptide-hybrided upconversion mesoporous silica nanoparticles for bortezomib/p53 delivery and apoptosis induction[J]. Colloids Surf B: Biointerfaces, 2020, 186: 110674 [17] Yu LD, Lin H, Lu XY, et al. Multifunctional mesoporous silica nanoprobes: Material chemistry-based fabrication and bio-Imaging functionality[J]. Adv Ther, 2019, 1: 18-28 [18] Murugan C, Venkatesan S, Kannan S.Cancer therapeutic proficiency of dual-targeted mesoporous silica nanocomposite endorses combination drug delivery [J].ACS Omega,2017,2(11): 7959-7975 [19] Serpell CJ, Rutte RN, Geraki K, et al.Carbon nanotubes allow capture of krypton, barium and lead for multichannel biological X-ray fluorescence imaging[J]. Nat Commun, 2016, 7: 13118 [20] Shen Y T,Liang L J, Zhang S Q, et al.Organelle-targeting gold nanorods for macromolecular profiling of subcellular organelles and enhanced cancer cell killing[J].ACS App Mater Interfaces, 2018,10(9): 7910-7918 [21] Yang C,Neshatianl M, van Prooijen M, et al.Cancer nanotechnology: Enhanced therapeutic response using peptide-modified gold nanoparticles[J]. J Nanosci Nanotechnol, 2014, 14(7): 4813-4819 [22] Khan SA, Shahid S, Lee CS. Green synthesis of gold and silver nanoparticles using leaf extract of clerodendruminerme; characterization, antimicrobial, and antioxidant activities[J]Biomolecules, 2020, 10(6): 835 [23] Tkachenko AG, Xie H, Coleman D, et al.Multifunctional gold nanoparticle-peptide complexes for nuclear targeting[J]. J Am Chem Soc, 2003, 125(16): 4700-4701 [24] Austin L A, Kang B, Yen C W, et al. Nuclear targeted silver nanospheres perturb the cancer cell cycle differently than those of nanogold [J]. Bioconjug Chem,2011, 22(11): 2324-2331 [25] Zhang LY, Li MF, Zhou Q, et al. Computed tomography and photoacoustic imaging guided photodynamic therapy against breast cancer based on mesoporous platinum with insitu oxygen generation ability [J]. Acta Pharm Sin B, 2020, 10(9): 1719-1729 [26] Mlodarczyk MT, Dragulska SA, Camacho-Vanegas O, et al. Platinum (II) complex-nuclear localization sequence peptide hybrid for overcoming platinum resistance in cancer therapy [J].ACS Biomater Sci Eng, 2018, 4(2): 463-467 [27] Ghaffari M, Dehghan G, Baradaran B, et al. Co-delivery of curcumin and Bcl-2 siRNA by PAMAM dendrimers for enhancement of the therapeutic efficacy in HeLa cancer cells [J]. Colloids Surf B Biointerfaces, 2020, 188:110762 [28] Ma AQ, Chen HQ,Cui YH, et al. Metalloporphyrin complex-based nanosonosensitizers for deep-tissue tumor theranostics by noninvasive sonodynamic therapy[J].Small,2019,15(5): e1804028 [29] Zhang R, Song XJ, Liang C, et al. Catalase-loaded cisplatin-prodrug-constructed liposomes to overcome tumor hypoxia for enhanced chemo-radiotherapy of cancer [J]. Biomaterials, 2017, 138: 13-21 [30] Yeon JK,Haribalan P,Verónica,et al.Photoluminescent and self-assembled hyaluronic acid-zinc oxide-ginsenoside Rh2 nanoparticles and their potential caspase-9 apoptotic mechanism Towards cancer cell Lines[J]. Int J Nanomedicine, 2019, 14: 8195-8208 [31] Gessner I, Neundorf I.Nanoparticles modified with cell-penetrating peptides: Conjugation mechanisms, physicochemical properties, and application in cancer diagnosis and therapy [J]. Int J Mol Sci, 2020, 21(7): 2536 [32] Shi X L, Zhu K Y, Ye Z D, et al.VCP/p97 targets the nuclear export and degradation of p27Kip1 during G1 to S phase transition [J]. FASEB J, 2020, 34(4): 5193-5207 [33] Cheng Y, Sun CL, Liu R, et al. A multifunctional peptide-conjugated AIEgen for efficient and sequential targeted gene delivery into the nucleus [J].Angew Chem Int Ed Engl, 2019,58 (15): 5049-5053 [34] Hao XF, Li Q, Guo JT, et al. Multifunctional gene carriers with enhanced specific penetration and nucleus accumulation to promote neovascularization of HUVECs in vivo[J].ACS Appl Mater Interfaces, 2017,9(41): 35613-35627 [35] Yu Z Z, Pan W, Li N, et al. A nuclear targeted dual-photosensitizer for drug-resistant cancer therapy with NIR activated multiple ROS [J]. Chem Sci, 2016, 7(7): 4237-4244 [36] Bannister A, Dissanayake D, Kowalewski A,et al. Modulation of the microtubule network for optimization of nanoparticle dynamics for the advancement of cancer nanomedicine[J]. Bioengineering (Basel), 2020, 7(2):56-72 [37] Ren XX, Yi Z, Sun Z, et al. Natural polysaccharide-incorporated hydroxyapatite as size-changeable, nuclear-targeted nanocarrier for efficient cancer therapy[J]. Biomater Sci, 2020, 8(19):5390-5401 [38] TammamS N, Azzazy HME, Lamprecht Alf, et al. The effect of nanoparticle size and NLS density on nuclear targeting in cancer and normal cells; impaired nuclear import and aberrant nanoparticle intracellular trafficking in glioma [J].J Control Release, 2017, 253: 30-36 [39] Liu Y, Wang J Q,Xiong QQ, et al. Nano-bio interactions in cancer: From therapeutics delivery to early detection [J]. Acc Chem Res, 2021, 54(2):291-301 [40] Medina MA, Oza G, Sharma A,et al.Triple-negative breast cancer: A review of conventional and advanced therapeutic strategies[J]. Int J Environ Res, 2020,17(6): 2078 [41] Qiu RN, Qian F, Wang X F, et al. Targeted delivery of 20(S)-ginsenoside Rg3-based polypeptide nanoparticles to treat colon cancer[J].Biomed Microdevices, 2019,21(1): 18 [42] Zhou HC, Lv SX, Zhang DW, et al.A polypeptide based podophyllotoxin conjugate for the treatment of multi drug resistant breast cancer with enhanced efficiency and minimal toxicity [J]. Acta Biomater, 2018, 73: 388-399 [43] Dong Y, Liao HZ, FH, et al.pH sensitive shell-core platform block DNA repair pathway to amplify irreversible DNA damage of triple negative breast cancer[J].ACS Appl Mater Interfaces, 2019, 11(42): 38417-38428