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Engineering Nanoparticles for Targeted Delivery of Nucleic Acid Therapeutics in Tumor

2018; Cell Press; Volume: 12; Linguagem: Inglês

10.1016/j.omtm.2018.09.002

ISSN

2329-0501

Autores

Yao Xiao, Kun Shi, Ying Qu, Bingyang Chu, Zhiyong Qian,

Tópico(s)

Nanoparticle-Based Drug Delivery

Resumo

In the past 10 years, with the increase of investment in clinical nano-gene therapy, there are many trials that have been discontinued due to poor efficacy and serious side effects. Therefore, it is particularly important to design a suitable gene delivery system. In this paper, we introduce the application of liposomes, polymers, and inorganics in gene delivery; also, different modifications with some stimuli-responsive systems can effectively improve the efficiency of gene delivery and reduce cytotoxicity and other side effects. Besides, the co-delivery of chemotherapy drugs with a drug tolerance-related gene or oncogene provides a better theoretical basis for clinical cancer gene therapy. In the past 10 years, with the increase of investment in clinical nano-gene therapy, there are many trials that have been discontinued due to poor efficacy and serious side effects. Therefore, it is particularly important to design a suitable gene delivery system. In this paper, we introduce the application of liposomes, polymers, and inorganics in gene delivery; also, different modifications with some stimuli-responsive systems can effectively improve the efficiency of gene delivery and reduce cytotoxicity and other side effects. Besides, the co-delivery of chemotherapy drugs with a drug tolerance-related gene or oncogene provides a better theoretical basis for clinical cancer gene therapy. Gene therapy is a promising therapeutic strategy aimed at altering or modifying defective and/or missing gene sequences to cure acquired or inherited diseases, including genetic disorders, cancer, cardiovascular diseases, and autoimmune disease, through introducing foreign genetic materials to cells, tissues, or organs.1Mulligan R.C. The basic science of gene therapy.Science. 1993; 260: 926-932Crossref PubMed Google Scholar RNAi, as a posttranslational gene regulation technology of gene therapy, can specifically inhibit the gene expression of interest triggered by small interfering RNA (siRNA), genome origin microRNA, and double-stranded small hairpin RNA (shRNA).2Sioud M. RNA interference: mechanisms, technical challenges, and therapeutic opportunities.Methods Mol. Biol. 2015; 1218: 1-15Crossref PubMed Scopus (2) Google Scholar In addition, RNA-programmed CRISPR/Cas9 mRNA has proven to be a versatile tool for therapeutic genome editing in mice, as recently reported.3Dominguez A.A. Lim W.A. Qi L.S. Beyond editing: repurposing CRISPR-Cas9 for precision genome regulation and interrogation.Nat. Rev. Mol. Cell Biol. 2016; 17: 5-15Crossref PubMed Scopus (243) Google Scholar, 4Hsu P.D. Lander E.S. Zhang F. 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Nusinersen, a modified antisense oligonucleotide to cure spinal muscular atrophy, following Formivisen and Mipomersen treating cytomegalovirus retinitis and high blood cholesterol, respectively, has been approved by the U.S. Food and Drug Administration (FDA).7Adams B.D. Parsons C. Walker L. Zhang W.C. Slack F.J. Targeting noncoding RNAs in disease.J. Clin. Invest. 2017; 127: 761-771Crossref PubMed Scopus (133) Google Scholar, 8Corey D.R. Nusinersen, an antisense oligonucleotide drug for spinal muscular atrophy.Nat. Neurosci. 2017; 20: 497-499Crossref PubMed Scopus (46) Google Scholar, 9Hoy S.M. Nusinersen: First Global Approval.Drugs. 2017; 77: 473-479Crossref PubMed Scopus (30) Google Scholar, 10Koo T. Wood M.J. Clinical trials using antisense oligonucleotides in duchenne muscular dystrophy.Hum. Gene Ther. 2013; 24: 479-488Crossref PubMed Scopus (81) Google Scholar The continued improvement of innovative DNA/RNA modifications and delivery carriers, such as nanoparticles (NPs), will aid to solve the challenges and barriers of DNA/RNA-based therapeutics. It is known that naked DNA/RNA molecules are rapidly degraded by nuclease, with a high clearance rate of kidney, poor efficiency of cell uptake by intravenous injection, and severe unintended side effects when off target.11Singh A. Trivedi P. Jain N.K. Advances in siRNA delivery in cancer therapy.Artif. Cells Nanomed. Biotechnol. 2018; 46: 274-283Crossref PubMed Scopus (4) Google Scholar Therefore, it is necessary to select a safe and stable transport carrier to deliver it to the target cells and tissues in clinical research. The transport carrier should meet these conditions: (1) it must protect DNA/RNA molecules from degrading and release with control; (2) it must be designed to increase the transfection efficiency, with the ability to penetrate deep into the tumor and reach tumor cells remote from the blood vessels for cellular internalization;12Sun Q. Sun X. Ma X. Zhou Z. Jin E. Zhang B. Shen Y. Van Kirk E.A. Murdoch W.J. Lott J.R. et al.Integration of nanoassembly functions for an effective delivery cascade for cancer drugs.Adv. Mater. 2014; 26: 7615-7621Crossref PubMed Scopus (102) Google Scholar, 13Sun Q. Radosz M. Shen Y. Challenges in design of translational nanocarriers.J. Control. Release. 2012; 164: 156-169Crossref PubMed Scopus (0) Google Scholar, 14Sun Q. Zhou Z. Qiu N. Shen Y. Rational Design of Cancer Nanomedicine: Nanoproperty Integration and Synchronization.Adv. 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Genet. 2000; 1: 91-99Crossref PubMed Google Scholar are more efficient than non-viral vectors in numerous cell lines due to their controlled nucleic acid packing and unpacking in or from the capsid, as well as the ability of the virus to overcome various extracellular and intracellular delivery barriers or defense mechanisms of the targeted cells; however, there are safety concerns about severe off-target immunogenicity, inflammatory response, and toxicity.16Somia N. Verma I.M. Gene therapy: trials and tribulations.Nat. Rev. Genet. 2000; 1: 91-99Crossref PubMed Google Scholar, 17Dufour B.D. McBride J.L. Intravascular AAV9 Administration for Delivering RNA Silencing Constructs to the CNS and Periphery.Methods Mol. Biol. 2016; 1364: 261-275Crossref PubMed Scopus (2) Google Scholar, 18Kootstra N.A. Verma I.M. Gene therapy with viral vectors.Annu. Rev. Pharmacol. Toxicol. 2003; 43: 413-439Crossref PubMed Scopus (200) Google Scholar, 19Nguyen J. Szoka F.C. Nucleic acid delivery: the missing pieces of the puzzle?.Acc. Chem. Res. 2012; 45: 1153-1162Crossref PubMed Scopus (180) Google Scholar In contrast, non-viral vectors, such as cationic lipid, polymers, and peptides using chemical entities that are able to mimic the main features of viral vectors, are able to compact and deliver nucleic acids in a similar manner. Also, these are much safer compared to viral vectors because the artificial design is usually not recognized (immediately) by the immune system. In addition, the chemical structure is controllable and easier to scale up and synthesize commercially.20Kullberg M. McCarthy R. Anchordoquy T.J. Systemic tumor-specific gene delivery.J. Control. Release. 2013; 172: 730-736Crossref PubMed Scopus (20) Google Scholar, 21Mintzer M.A. Simanek E.E. Nonviral vectors for gene delivery.Chem. Rev. 2009; 109: 259-302Crossref PubMed Scopus (1613) Google Scholar, 22Yin H. Kanasty R.L. Eltoukhy A.A. Vegas A.J. Dorkin J.R. Anderson D.G. Non-viral vectors for gene-based therapy.Nat. Rev. Genet. 2014; 15: 541-555Crossref PubMed Scopus (1033) Google Scholar However, there are still some problems with non-viral carriers to confront. The first is how to improve the efficiency of passive targeting, namely, the enhanced permeability and retention (EPR) effect. The EPR effect is the unique and most crucial phenomenon occurring in tumor tissue, with excessive production of vascular mediators and extravasation of macromolecules from blood vessels into the tumor tissue interstitium.23Matsumura Y. Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.Cancer Res. 1986; 46: 6387-6392PubMed Google Scholar Maeda et al.24Maeda H. Tsukigawa K. Fang J. A Retrospective 30 Years After Discovery of the Enhanced Permeability and Retention Effect of Solid Tumors: Next-Generation Chemotherapeutics and Photodynamic Therapy--Problems, Solutions, and Prospects.Microcirculation. 2016; 23: 173-182Crossref PubMed Scopus (0) Google Scholar summarized the characteristics of the EPR effect of nanomedicines and macromolecular drugs in most, if not all, solid tumors, including biocompatibility, property size (over 40 kDa), weakly negative to near neutral, maintain at least 30 min to achieve tumor site and cleared rapidly in cells, then drug release. The second one is choosing a highly specific molecular target to even a single epitopic antigen, receptor, or kinase, which can modify NPs to target tissue and enhance the therapeutic efficacy,25Danhier F. To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine?.J. Control. 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In addition, we highlight the exploitation and discovery of different NPs and their modification in DNA/RNA delivery to discover more efficiency and safer NPs in gene delivery. In the last decade, several biotechnology companies have invested massive manpower, physical resources, and funds in NPs-based gene therapeutics. The NPs-RNA complex is intended to enhance its circulation, promoting safe delivery to the desired location and silencing of the target mRNAs.28Oliveira C. Ribeiro A.J. Veiga F. Silveira I. Recent Advances in Nucleic Acid-Based Delivery: From Bench to Clinical Trials in Genetic Diseases.J. Biomed. Nanotechnol. 2016; 12: 841-862Crossref PubMed Scopus (16) Google Scholar Most of the NPs-based siRNA/microRNA delivery systems currently are approved for clinical trials in cancer therapy, virus infection, and other diseases (Table 1).Table 1The siRNA/MicroRNA-Based Drugs Targeting Different Diseases in Clinical TrialsDiseaseTargetVehicleDrug NameSponsorClinicalTrials.gov Identifier (Phase)CancerHC, ST, ACC, GNTsiRNA target PLK1lipid nanoparticleTKM 080301Tekmira PharmaceuticalsNCT02191878 (I/II)NCT01262235 (I/II)NCT01437007 (I)ST, MM, NHLsiRNA target MYClipid nanoparticleDCR-MYCDicerna PharmaceuticalsNCT02110563 (I) NCT02314052 (I/II)STsiRNA target RRM2polymer nanoparticleCALAA-01Calando PharmaceuticalsNCT00689065 (I)STsiRNA target EphA2liposomesiRNA-EphA2-DOPCM.D.Anderson Cancer CenterNCT01591356 (I)Leukemiaantisense target GRB-2neutral liposomesBP1001Bio-Path HoldingsNCT01159028 (I)ASC, PCsiRNA target PKN3lipid nanoparticleAtu027Silence TherapeuticsNCT01808638 (I/II) NCT00938574 (I)PDA, PCsiRNA target K-RASbiodegradable polymer matrixsiG12D LODERSilenseedNCT01188785 (I) NCT01676259 (II)GlioblastomasiRNA target p53nanoparticle (NPs)Temozolomide/SGT-53SynerGene TherapeuticsNCT02340156Lung cancersiRNA target Fus1DOTAP-CholFus1/ErlotinibGenprexNCT01455389 (I/II)HCsiRNA target CEBPAliposomal nanoparticleMTL-CEBPAMina AlphaNCT02716012 (I)GlioblastomasiRNA target Bcl2L12spherical gold nanoparticleNU-0129Northwestern UniversityNCT03020017 (early I)IMGsiRNA target UGT1A1*28nanoliposomalCPT-11University of California, San FranciscoNCT00734682 (I)Advanced, metastatic cancer, STshRNA STMN1BIV-lipoplexpbi-shRNA STMN1 LPStrike BioNCT01505153 (I)Ewing's sarcomashRNA EWS/FLI1 type 1BIV-lipoplexpbi-shRNA EWS/FLI1 Type 1 LPXStrike BioNCT02736565 (I)NReIF5AK50R plasmid eIF5A siRNApolyethylenimineSNS01-TSenesco TechnologiesNCT01435720 (II)MPM, NSCLCmicroRNA -16 mimic target EGFREDVTargomiRsAsbestos Diseases Research FoundationNCT02369198 (I)Virus infectionEVDsiRNA target VP24, and VP35 regions, EBOV polymerase inhibitorlipid nanoparticleFavipiravirINSERM, FranceNCT02329054 (II)Other DiseaseHepatic fibrosissiRNA target HSP47lipid nanoparticleND-L02 s0201 injectionBristol-Myers SquibbNCT02227459 (Ib/II)HypercholesterolemiasiRNA target APOBlipid nanoparticlePRO-040201Tekmira PharmaceuticalsNCT00927459 (I), terminatedSource: https://clinicaltrials.gov. ACC, adrenocortical carcinoma; ASC, advanced solid cancer; GNT, gastrointestinal neuroendocrine tumors; HC, hepatocellular carcinoma; MM, multiple myeloma; MPM, malignant pleural mesothelioma; NHL, non-Hodgkins lymphoma; NSCLC, non-small-cell lung cancer; PC, pancreatic cancer; PDA, pancreatic ductal adenocarcinoma; ST, solid tumor; ALC, advanced liver cancer; SCLC, squamous cell lung cancer; IMG, intracranial malignant glioma; NR, not recorded; EGFR, epidermal growth factor receptor; GRB-2, Growth Factor Receptor Bound Protein-2; RRM2, Ribonucleotide Reductase Regulatory Subunit M2; PLK1,Polo-Like Kinase 1; HSP47, Heat Shock Protein 47; EphA2, Ephrin type-A receptor 2; eIf5A, Eukaryotic translation initiation factor 5A-1; EDV, EnGeneIC Delivery Vehicle; CEBPA,CCAAT/enhancer-binding protein alpha; BIV-lipoplex, bilamellar invaginated vesicle lipoplex; EVD, Ebola virus disease; PKN3, protein kinase N3; K-Ras oncogene, Kirsten rat sarcoma viral oncogene; APOB, apolipoprotein B; VP24, virus protein 24; VP35, virus protein 3. Open table in a new tab Source: https://clinicaltrials.gov. ACC, adrenocortical carcinoma; ASC, advanced solid cancer; GNT, gastrointestinal neuroendocrine tumors; HC, hepatocellular carcinoma; MM, multiple myeloma; MPM, malignant pleural mesothelioma; NHL, non-Hodgkins lymphoma; NSCLC, non-small-cell lung cancer; PC, pancreatic cancer; PDA, pancreatic ductal adenocarcinoma; ST, solid tumor; ALC, advanced liver cancer; SCLC, squamous cell lung cancer; IMG, intracranial malignant glioma; NR, not recorded; EGFR, epidermal growth factor receptor; GRB-2, Growth Factor Receptor Bound Protein-2; RRM2, Ribonucleotide Reductase Regulatory Subunit M2; PLK1,Polo-Like Kinase 1; HSP47, Heat Shock Protein 47; EphA2, Ephrin type-A receptor 2; eIf5A, Eukaryotic translation initiation factor 5A-1; EDV, EnGeneIC Delivery Vehicle; CEBPA,CCAAT/enhancer-binding protein alpha; BIV-lipoplex, bilamellar invaginated vesicle lipoplex; EVD, Ebola virus disease; PKN3, protein kinase N3; K-Ras oncogene, Kirsten rat sarcoma viral oncogene; APOB, apolipoprotein B; VP24, virus protein 24; VP35, virus protein 3. CALAA-01 is a polymer-based NPs siRNA delivery system containing a linear, cationic cyclodextrin-based polymer and a siRNA that targets the M2 subunit of ribonucleotide reductase (RRM2) (Figure 1A). Adamantane polyethylene glycol (PEG) was used as a surface modifier on the NPs to provide steric stabilization and a targeting ligand (human protein transferrin) on its surface as a positive target. The cationic polymer interacts electrostatically with anionic siRNA to assemble into nanocomplexes below approximately 100 nm in diameter that protect the siRNA from nuclease degradation in serum. The siRNA-containing nanocomplexes are targeted to cells that overexpress the transferrin receptor (TfR), and then anti-R2 suppresses RRM2 expression, resulting in cell-cycle arrest and cell death.29Heidel J.D. Liu J.Y.C. Yen Y. Zhou B. Heale B.S.E. Rossi J.J. Bartlett D.W. Davis M.E. Potent siRNA inhibitors of ribonucleotide reductase subunit RRM2 reduce cell proliferation in vitro and in vivo.Clin. Cancer Res. 2007; 13: 2207-2215Crossref PubMed Scopus (107) Google ScholarThe trial has been terminated due to 21% of the patients having an adverse event because of drug instability (specifically the transferrin-targeting ligand).30Zuckerman J.E. Davis M.E. Clinical experiences with systemically administered siRNA-based therapeutics in cancer.Nat. Rev. Drug Discov. 2015; 14: 843-856Crossref PubMed Scopus (142) Google Scholar Tolerable dose, siRNA plasma concentration, and elevated plasma levels of cytokines have no association with adverse events. In addition, a dose-dependent accumulation of CALAA-01 within tumors, but not adjacent tissue, was found in CALAA-01-specific staining, and the expression of RRM2 in protein and mRNA level were inhibited effectively.31Zuckerman J.E. Gritli I. Tolcher A. Heidel J.D. Lim D. Morgan R. Chmielowski B. Ribas A. Davis M.E. Yen Y. Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA.Proc. Natl. Acad. Sci. USA. 2014; 111: 11449-11454Crossref PubMed Scopus (132) Google Scholar Thus, how not only to engineer nanomedicines to make them effectively target tumor tissues but also to choose an appropriate delivery system are the keys to developing new-generation nanomedicines of high therapeutic efficacy. siG12D LODER is composed of Local Drug EluteR (LODER), a novel biodegradable polymeric matrix that shields drugs against enzymatic degradation and siRNA against G12D-mutated KRAS (siG12D), which is released by LODER slowly (Figure 1B).32Golan T. Khvalevsky E.Z. Hubert A. Gabai R.M. Hen N. Segal A. Domb A. Harari G. David E.B. Raskin S. et al.RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients.Oncotarget. 2015; 6: 24560-24570Crossref PubMed Scopus (50) Google Scholar, 33Titze-de-Almeida R. 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Liposomal Formulations in Clinical Use: An Updated Review.Pharmaceutics. 2017; 9: E12Crossref PubMed Scopus (0) Google Scholar In this delivery system, PLK1 is a protein overexpressed in cancer cells promoting an uncontrolled cell proliferation,39Liu X. Targeting Polo-Like Kinases: A Promising Therapeutic Approach for Cancer Treatment.Transl. Oncol. 2015; 8: 185-195Abstract Full Text Full Text PDF PubMed Google Scholar and researchers used siRNA-silencing PLK1 molecules incorporating into the aqueous inner part with the help of cationic lipids (1,2-dilinoleyloxy-N,N-dimethyl-3-aminopropane,DlinDMA). Helper lipids with DSPC (1,2-distear-oyl-sn-glycero-3-phosphocholine) promote the release of siRNAs from SNALPs in the cell cytoplasm. Polyethylene glycosylated lipids (PEG-C-DMA) offer an external surface that is more hydrophilic and neutral, for stability and crossing barriers. Cholesterol helps to stabilize the lipid particle formulation.40Kanasty R. Dorkin J.R. Vegas A. Anderson D. Delivery materials for siRNA therapeutics.Nat. Mater. 2013; 12: 967-977Crossref PubMed Scopus (743) Google Scholar Nowadays, some of these trials are in phase III and the results will hopefully be approved. Engineering NPs carriers has received wide attention in gene delivery due to their outstanding characteristics, including diverse modifications and high stability biocompatibility to adapt desirable properties in particle forms. Among the nanopaticles used in gene delivery carriers, the cationic polymer and lipid were the most widely used polymer for the delivery of DNA and RNA molecules. Naked siRNA/microRNA permeating the cell membrane is blocked by its size and negative charge. Thus, using the electropositivity of cationic polymer leads to the formation of complexes containing siRNA/microRNA molecules promoting cell uptake and preventing degradation by RNase. Most complexes interact with the cell membrane electrostatically, because of the anionic cell surface proteoglycans, and enter into cells. For cell uptake, clathrin- and caveolae-mediated endocytosis, which are energy-dependent and controlled by the cell internalized molecules, are the common processes (Figure 2); the other occurs in phagocytes (macrophages, dendritic cells, and neutrophils), and the sizes of engulfing particles are larger than 0.5 μm, driven by actin.41Geiser M. Update on macrophage clearance of inhaled micro- and nanoparticles.J. Aerosol Med. Pulm. Drug Deliv. 2010; 23: 207-217Crossref PubMed Scopus (0) Google Scholar, 42Oh N. Park J.H. Endocytosis and exocytosis of nanoparticles in mammalian cells.Int. J. Nanomedicine. 2014; 9: 51-63PubMed Google Scholar, 43Lee H.Y. Mohammed K.A. Nasreen N. Nanoparticle-based targeted gene therapy for lung cancer.Am. J. Cancer Res. 2016; 6: 1118-1134PubMed Google Scholar, 44Jiang X. Röcker C. Hafner M. Brandholt S. Dörlich R.M. 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Several temperature- and pH-sensitive polymers or other smart polymers rapidly used in gene delivery to enhance cell uptake and lysosomal escape are introduced in Different Stimuli-Responsive Gene Delivery Systems. For shRNA, the carrier vector must carry it into the nucleus of the host cell, and nuclear localization sequences (NLSs) have been utilized. There are reports of the transfection efficiencies of cationic DNA nanocarriers or polycations coupled with NLS derived from the SV40 large T antigen, which can be recognized and go through the nuclear pore complex (NPC).48Dean D.A. Dean B.S. Muller S. Smith L.C. Sequence requirements for plasmid nuclear import.Exp. Cell Res. 1999; 253: 713-722Crossref PubMed Scopus (161) Google Scholar, 49Aronsohn A.I. Hughes J.A. Nuclear localization signal peptides enhance cationic liposome-mediated gene therapy.J. Drug Target. 1998; 5: 163-169Crossref PubMed Google Scholar, 50Collins E. Birchall J.C. Williams J.L. Gumbleton M. Nuclear localisation and pDNA condensation in non-viral gene delivery.J. Gene Med. 2007; 9: 265-274Crossref PubMed Scopus (29) Google Scholar A peptide or protein such as Histon H1 can also improve the efficiency of entering into the nucleus.51Zaitsev S. Buchwalow I. Haberland A. Tkachuk S. Zaitseva I. Haller H. Böttger M. Histone H1-mediated transfection: role of calcium in the cellular uptake and intracellular fate of H1-DNA complexes.Acta Histochem. 2002; 104: 85-92Crossref PubMed Google Scholar Besides, sugar residue can also transport cargoes into the nucleus, and the pathway is used by neoglycoproteins to enter the nucleus. Lactosylated polylysine (PLL)/cDNA complex induced nuclear localization by binding to a potential lectin-like shuttling protein with galactose/lactose specificity, and this binding interaction was suggested to trigger the nuclear internalization of the complex.52Klink D.T. Chao S. Glick M.C. Scanlin T.F. Nuclear translocation of lactosylated poly-L-lysine/cDNA complex in cystic fibrosis airway epithelial cells.Mol. Ther. 2001; 3: 831-841Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 53Grandinetti G. Reineke T.M. Exploring the mechanism of plasmid DNA nuclear internalization with polymer-based vehicles.Mol. Pharm. 2012; 9: 2256-2267Crossref PubMed Scopus (36) Google Scholar Some cationic polymers like PEI and T443, a poly-(glycoamidoamine), are capable of inducing nuclear membrane permeability, but they also have the highest level of cytotoxicity.53Grandinetti G. Reineke T.M. Exploring the mechanism of plasmid DNA nuclear internalization with polymer-based vehicles.Mol. Pharm. 2012; 9: 2256-2267Crossref PubMed Scopus (36) Google Scholar Despite the increasing biocompatibility of the material and the decreasing side effects, NPs-mediated toxicity still exists. 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