Lung cancer is one of the leading causes of deaths in the United States, but currently available therapies for lung cancer are associated with reduced efficacy and adverse side effects. Small interfering RNA (siRNA) can knock down the expression of specific genes and result in therapeutic efficacy in lung cancer. Recently, mTOR siRNA has been shown to induce apoptosis in NSCLC cell lines but its use is limited due to poor stability in biological conditions.
In this study, we modified an aminoglyocisde-derived cationic poly (amino-ether) by introducing a thiol group using Traut’s reagent to generate a bio-reducible modified–poly (amino-ether) (mPAE). The mPAE polymer was used to encapsulate mTOR siRNA by nanoprecipitation method, resulting in the formation of stable and bio-reducible nanoparticles (NPs) which possessed an average diameter of 114 nm and a surface charge of approximately +27 mV.
The mTOR siRNA showed increased release from the mTS-mPAE NPs in the presence of 10 mM glutathione (GSH). The polymeric mTS-mPAE-NPs were also capable of efficient gene knockdown (60 and 64%) in A549 and H460 lung cancer cells, respectively without significant cytotoxicity at 30 μg/ml concentrations. The NPs also showed time-dependent cellular uptake for up to 24 h as determined using flow cytometry. Delivery of the siRNA using these NPs also resulted in significant inhibition of A549 and H460 cell proliferation in vitro, respectively.
The results demonstrate that the mPAE polymer based NPs show strong potential for siRNA delivery to lung cancer cells. It is anticipated that future modification can help improve the efficacy of nucleic acid delivery, leading to higher inhibition of lung cancer growth in vitro and in vivo.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.
Gandhi NS, Tekade RK, Chougule MB. Nanocarrier mediated delivery of siRNA/miRNA in combination with chemotherapeutic agents for cancer therapy: current progress and advances. J Control Release. 2014;194:238–56.
Nichols L, Saunders R, Knollmann FD. Causes of death of patients with lung cancer. Arch Pathol Lab Med. 2012;136:1552–7.
Key Statistics for Lung Cancer, in, 2017. http://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2017.html. Assessed 1 Jul 2017
Gadgeel SM, Ramalingam SS, Kalemkerian GP. Treatment of lung cancer. Radiol Clin N Am. 2012;50:961–74.
Artal Cortés Á, Calera Urquizu L, Hernando Cubero J. Adjuvant chemotherapy in non-small cell lung cancer: state-of-the-art. Translational Lung Cancer Research. 2015;4:191–7.
Links M, Brown R. Clinical relevance of the molecular mechanisms of resistance to anti-cancer drugs. Expert Rev Mol Med. 1999;1999:1–21.
Moding EJ, Kastan MB, Kirsch DG. Strategies for optimizing the response of cancer and normal tissues to radiation. Nat Rev Drug Discov. 2013;12:526–42.
Brannon-Peppas L, Blanchette JO. Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev. 2004;56:1649–59.
Kozielski KL, Tzeng SY, De Mendoza BA, Green JJ. Bioreducible cationic polymer-based nanoparticles for efficient and environmentally triggered cytoplasmic siRNA delivery to primary human brain cancer cells. ACS Nano. 2014;8:3232–41.
Dobashi Y, Watanabe Y, Miwa C, Suzuki S, Koyama S. Mammalian target of rapamycin: a central node of complex signaling cascades. Int J Clin Exp Pathol. 2011;4:476–95.
Goschzik T, Gessi M, Denkhaus D, Pietsch T. PTEN mutations and activation of the PI3K/Akt/mTOR signaling pathway in papillary tumors of the pineal region. J Neuropathol Exp Neurol. 2014;73:747–51.
Pallet N, Legendre C. Adverse events associated with mTOR inhibitors. Expert Opin Drug Saf. 2013;12:177–86.
Sadowski K, Kotulska K, Jóźwiak S. Management of side effects of mTOR inhibitors in tuberous sclerosis patients. Pharmacol Rep. 2016;68:536–42.
Matsubara H, Sakakibara K, Kunimitsu T, Matsuoka H, Kato K, Oyachi N, et al. Non-small cell lung carcinoma therapy using mTOR-siRNA. Int J Clin Exp Pathol. 2012;5:119–25.
Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391:806–11.
Kuwabara PE, Coulson A. RNAi – prospects for a general technique for determining gene function. Parasitol Today. 2000;16(8):347–49.
Li SD, Chono S, Huang L. Efficient oncogene silencing and metastasis inhibition via systemic delivery of siRNA. Mol Ther. 2008;16:942–6.
Zeng L, Li J, Wang Y, Qian C, Chen Y, Zhang Q, et al. Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosis using a nanomedicine strategy for the effective treatment of pancreatic cancer. Nanomedicine. 2014;10:463–72.
Fresta M, Villari A, Puglisi G, Cavallaro G. 5-fluorouracil: various kinds of loaded liposomes: encapsulation efficiency, storage stability and fusogenic properties. Int J Pharm. 1993;99:145–56.
Youngren-Ortiz SR, Gandhi NS, Espana-Serrano L, Chougule MB. Aerosol delivery of siRNA to the lungs. Part 1: rationale for gene delivery systems. Kona. 2016;33:63–85.
Lee H, Kim Y-H. Nanobiomaterials for pharmaceutical and medical applications. Arch Pharm Res. 2014;37:1–3.
Lee YS, Kim SW. Bioreducible polymers for therapeutic gene delivery. J Control Release. 2014;190:424–39.
Kosuge H, Sherlock SP, Kitagawa T, Dash R, Robinson JT, Dai H, et al. Near infrared imaging and photothermal ablation of vascular inflammation using single-walled carbon nanotubes. J Am Heart Assoc. 2012;1:e002568.
Son S, Namgung R, Kim J, Singha K, Kim WJ. Bioreducible polymers for gene silencing and delivery. Acc Chem Res. 2012;45:1100–12.
Kim T-i, Kim SW. Bioreducible polymers for gene delivery. React Funct Polym. 2011;71:344–9.
Barua S, Joshi A, Banerjee A, Matthews D, Sharfstein ST, Cramer SM, et al. Parallel synthesis and screening of polymers for nonviral gene delivery. Mol Pharm. 2008;6:86–97.
Gosnell H, Kasman LM, Potta T, Vu L, Garrett-Mayer E, Rege K, et al. Polymer-enhanced delivery increases adenoviral gene expression in an orthotopic model of bladder cancer. J Control Release. 2014;176:35–43.
Miryala B, Zhen Z, Potta T, Breneman CM, Rege K. Parallel synthesis and quantitative structure–activity relationship (QSAR) modeling of aminoglycoside-derived Lipopolymers for transgene expression. ACS Biomaterials Science & Engineering. 2015;1:656–68.
Miryala B, Feng Y, Omer A, Potta T, Rege K. Quaternization enhances the transgene expression efficacy of aminoglycoside-derived polymers. Int J Pharm. 2015;489:18–29.
Ramos J, Rege K. Transgene delivery using poly(amino ether)-gold nanorod assemblies. Biotechnol Bioeng. 2012;109:1336–46.
Ramos J, Rege K. Comparative investigation of polymeric and nanoparticle vehicles for transgene delivery. Nano LIFE. 2016;06:1641001.
Ramos J, Rege K. Poly(aminoether)–gold Nanorod assemblies for shRNA plasmid-induced gene silencing. Mol Pharm. 2013;10:4107–19.
Huang H-C, Barua S, Kay DB, Rege K. Simultaneous enhancement of Photothermal stability and gene delivery efficacy of gold Nanorods using polyelectrolytes. ACS Nano. 2009;3:2941–52.
Godeshala S, Nitiyanandan R, Thompson B, Goklany S, Nielsen DR, Rege K. Folate receptor-targeted aminoglycoside-derived polymers for transgene expression in cancer cells. Bioengineering & Translational Medicine. 2016;1:220–31.
Miryala B, Godeshala S, Grandhi TSP, Christensen MD, Tian Y, Rege K. Aminoglycoside-derived amphiphilic nanoparticles for molecular delivery. Colloids Surf B: Biointerfaces. 2016;146:924–37.
Kommareddy S, Amiji M. Preparation and evaluation of thiol-modified gelatin nanoparticles for intracellular DNA delivery in response to glutathione. Bioconjug Chem. 2005;16:1423–32.
King TP, Li Y, Kochoumian L. Preparation of protein conjugates via intermolecular disulfide bond formation. Biochemistry. 1978;17:1499–506.
Riddles PW, Blakeley RL, Zerner B. Ellman's reagent: 5,5′-dithiobis(2-nitrobenzoic acid)—a reexamination. Anal Biochem. 1979;94:75–81.
Vichai V, Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 2006;1:1112–6.
Singh B, Maharjan S, Park TE, Jiang T, Kang SK, Choi YJ, et al. Tuning the buffering capacity of polyethylenimine with glycerol molecules for efficient gene delivery: staying in or out of the endosomes. Macromol Biosci. 2015;15:622–35.
Benjaminsen RV, Mattebjerg MA, Henriksen JR, Moghimi SM, Andresen TL. The possible “proton sponge” effect of polyethylenimine (PEI) does not include change in lysosomal pH. Mol Ther. 2013;21:149–57.
Alshamsan A. Nanoprecipitation is more efficient than emulsion solvent evaporation method to encapsulate cucurbitacin I in PLGA nanoparticles. Saudi Pharmaceutical Journal. 2014;22:219–22.
Bilati U, Allémann E, Doelker E. Development of a nanoprecipitation method intended for the entrapment of hydrophilic drugs into nanoparticles. Eur J Pharm Sci. 2005;24:67–75.
AccuBlue high sensitivity dsDNA quantification kit (Biotium), in, www.biotium.com, 2016.
Lushchak VI. Glutathione homeostasis and functions: potential targets for medical interventions. J Amino Acids. 2012;2012:1–26.
Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr. 2004;134:489–92.
Fu Y, Kao WJ. Drug release kinetics and transport mechanisms of non-degradable and degradable polymeric delivery systems. Expert Opinion on Drug Delivery. 2010;7:429–44.
Hara K, Tsujimoto H, Huang CC, Kawashima Y, Ando R, Kusuoka O, et al. Ultrastructural and Immunohistochemical studies on uptake and distribution of FITC-conjugated PLGA nanoparticles administered Intratracheally in rats. J Toxicol Pathol. 2012;25:19–26.
Liu CW, Lin WJ. Polymeric nanoparticles conjugate a novel heptapeptide as an epidermal growth factor receptor-active targeting ligand for doxorubicin. Int J Nanomedicine. 2012;7:4749–67.
Yu MK, Park J, Jon S. Targeting strategies for multifunctional nanoparticles in cancer imaging and therapy. Theranostics. 2012;2:3–44.
Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys. 1959;82:70–7.
Beyerle A, Irmler M, Beckers J, Kissel T, Stoeger T. Toxicity pathway focused gene expression profiling of PEI-based polymers for pulmonary applications. Mol Pharm. 2010;7:727–37.
Liang W, Lam JKW. Endosomal escape pathways for non-viral nucleic acid delivery systems. In: Ceresa B, editor. Molecular regulation of endocytosis. Rijeka: InTech; 2012. p. Ch. 17.
Shi J, Schellinger JG, Johnson RN, Choi JL, Chou B, Anghel EL, et al. Influence of histidine incorporation on buffer capacity and gene transfection efficiency of HPMA-co-oligolysine brush polymers. Biomacromolecules. 2013;14:1961–70.
Tseng WC, Tang CH, Fang TY. The role of dextran conjugation in transfection mediated by dextran-grafted polyethylenimine. The Journal of Gene Medicine. 2004;6:895–905.
Shim MS, Kwon YJ. Acid-responsive linear polyethylenimine for efficient, specific, and biocompatible siRNA delivery. Bioconjug Chem. 2009;20:488–99.
Mok H, Lee SH, Park JW, Park TG. Multimeric small interfering ribonucleic acid for highly efficient sequence-specific gene silencing. Nat Mater. 2010;9:272–8.
Kim J, Kim SW, Kim WJ. PEI-g-PEG-RGD/small interference RNA polyplex-mediated silencing of vascular endothelial growth factor receptor and its potential as an anti-angiogenic tumor therapeutic strategy. Oligonucleotides. 2011;21:101–7.
Ekman S, Wynes MW, Hirsch FR. The mTOR pathway in lung cancer and implications for therapy and biomarker analysis. J Thorac Oncol. 2012;7:947–53.
Fumarola C, Bonelli MA, Petronini PG, Alfieri RR. Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer. Biochem Pharmacol. 2014;90:197–207.
Dang L, Liu J, Li F, Wang L, Li D, Guo B, et al. Targeted delivery Systems for Molecular Therapy in skeletal disorders. Int J Mol Sci. 2016;17:428.
Lin J, Alexander-Katz A. Cell membranes open “doors” for cationic nanoparticles/biomolecules: insights into uptake kinetics. ACS Nano. 2013;7:10799–808.
Kommareddy S, Amiji M. Poly(ethylene glycol)-modified thiolated gelatin nanoparticles for glutathione-responsive intracellular DNA delivery. Nanomedicine. 2007;3:32–42.
Lee D, Lee YM, Jeong C, Lee J, Kim WJ. Bioreducible Guanidinylated Polyethylenimine for efficient gene delivery. ChemMedChem. 2014;9:2718–24.
Wardman P, Dennis MF, Stratford MR, White J. Extracellular: intracellular and subcellular concentration gradients of thiols. Int J Radiat Oncol Biol Phys. 1992;22:751–4.
Carilho Torrao RBD, Dias IHK, Bennett SJ, Dunston CR, Griffiths HR. Healthy ageing and depletion of intracellular glutathione influences T cell membrane thioredoxin-1 levels and cytokine secretion. Chemistry Central Journal. 2013;7:150.
Breunig M, Hozsa C, Lungwitz U, Watanabe K, Umeda I, Kato H, et al. Mechanistic investigation of poly(ethylene imine)-based siRNA delivery: disulfide bonds boost intracellular release of the cargo. J Control Release. 2008;130:57–63.
Muthiah M, Che HL, Kalash S, Jo J, Choi SY, Kim WJ, et al. Formulation of glutathione responsive anti-proliferative nanoparticles from thiolated Akt1 siRNA and disulfide-crosslinked PEI for efficient anti-cancer gene therapy. Colloids Surf B: Biointerfaces. 2015;126:322–7.
Shen Y, Wang J, Li Y, Tian Y, Sun H, Ammar O, et al. Co-delivery of siRNA and paclitaxel into cancer cells by hyaluronic acid modified redox-sensitive disulfide-crosslinked PLGA-PEI nanoparticles. RSC Adv. 2015;5:46464–79.
Tai Z, Wang X, Tian J, Gao Y, Zhang L, Yao C, et al. Biodegradable Stearylated peptide with internal disulfide bonds for efficient delivery of siRNA in vitro and in vivo. Biomacromolecules. 2015;16:1119–30.
Erbacher P, Bettinger T, Brion E, Coll JL, Plank C, Behr JP, et al. Genuine DNA/polyethylenimine (PEI) complexes improve transfection properties and cell survival. J Drug Target. 2004;12:223–36.
Longo PA, Kavran JM, Kim MS, Leahy DJ. Transient mammalian cell transfection with polyethylenimine (PEI). Methods Enzymol. 2013;529:227–40.
Hou S, Ziebacz N, Wieczorek SA, Kalwarczyk E, Sashuk V, Kalwarczyk T, et al. Formation and structure of PEI/DNA complexes: quantitative analysis. Soft Matter. 2011;7:6967–72.
Hobel S, Aigner A. Polyethylenimine (PEI)/siRNA-mediated gene knockdown in vitro and in vivo. Methods Mol Biol. 2010;623:283–97.
Knight M, Miller A, Liu Y, Scaria P, Woodle M, Ittiprasert W. Polyethyleneimine (PEI) mediated siRNA gene silencing in the Schistosoma mansoni snail host, Biomphalaria glabrata. PLoS Negl Trop Dis. 2011;5:e1212.
Kang J-H, Tachibana Y, Kamata W, Mahara A, Harada-Shiba M, Yamaoka T. Liver-targeted siRNA delivery by polyethylenimine (PEI)-pullulan carrier. Bioorg Med Chem. 2010;18:3946–50.
Lee S-Y, Huh MS, Lee S, Lee SJ, Chung H, Park JH, et al. Stability and cellular uptake of polymerized siRNA (poly-siRNA)/polyethylenimine (PEI) complexes for efficient gene silencing. J Control Release. 2010;141:339–46.
Ibrahim AF, Weirauch U, Thomas M, Grunweller A, Hartmann RK, Aigner A. MicroRNA replacement therapy for miR-145 and miR-33a is efficacious in a model of colon carcinoma. Cancer Res. 2011;71:5214–24.
Meneksedag-Erol D, Tang T, Uludag H. Probing the effect of miRNA on siRNA-PEI Polyplexes. J Phys Chem B. 2015;119:5475–86.
Florea BI, Meaney C, Junginger HE, Borchard G. Transfection efficiency and toxicity of polyethylenimine in differentiated Calu-3 and nondifferentiated COS-1 cell cultures. AAPS pharmSci. 2002;4:E12.
Breunig M, Lungwitz U, Liebl R, Goepferich A. Breaking up the correlation between efficacy and toxicity for nonviral gene delivery. Proc Natl Acad Sci. 2007;104:14454–9.
Moghimi SM, Symonds P, Murray JC, Hunter AC, Debska G, Szewczyk A. A two-stage poly(ethylenimine)-mediated cytotoxicity: implications for gene transfer/therapy. Mol Ther. 2005;11:990–5.
Nimesh S, Goyal A, Pawar V, Jayaraman S, Kumar P, Chandra R, et al. Polyethylenimine nanoparticles as efficient transfecting agents for mammalian cells. J Control Release. 2006;110:457–68.
Pichon C, Goncalves C, Midoux P. Histidine-rich peptides and polymers for nucleic acids delivery. Adv Drug Deliv Rev. 2001;53:75–94.
Mehrotra S, Lee I, Chan C. Multilayer mediated forward and patterned siRNA transfection using linear-PEI at extended N/P ratios. Acta Biomater. 2009;5:1474–88.
Mishra S, Vaughn AD, Devore DI, Roth CM. Delivery of siRNA silencing Runx2 using a multifunctional polymer-lipid nanoparticle inhibits osteogenesis in a cell culture model of heterotopic ossification. Integr Biol (Camb). 2012;4:1498–507.
Shen J, Kim HC, Mu C, Gentile E, Mai J, Wolfram J, et al. Multifunctional gold nanorods for siRNA gene silencing and photothermal therapy. Advanced Healthcare Materials. 2014;3:1629–37.
Li T, Shen X, Chen Y, Zhang C, Yan J, Yang H, et al. Polyetherimide-grafted Fe(3)O(4)@SiO2(2) nanoparticles as theranostic agents for simultaneous VEGF siRNA delivery and magnetic resonance cell imaging. Int J Nanomedicine. 2015;10:4279–91.
Read ML, Singh S, Ahmed Z, Stevenson M, Briggs SS, Oupicky D, et al. A versatile reducible polycation-based system for efficient delivery of a broad range of nucleic acids. Nucleic Acids Res. 2005;33:e86.
Yoshino K, Nakamura K, Terajima Y, Kurita A, Matsuzaki T, Yamashita K, et al. Comparative studies of irinotecan-loaded polyethylene glycol-modified liposomes prepared using different PEG-modification methods. Biochimica et Biophysica Acta (BBA)-Biomembranes. 2012;1818:2901–7.
Conti DS, Brewer D, Grashik J, Avasarala S, da Rocha SRP. Poly(amidoamine) dendrimer Nanocarriers and their aerosol formulations for siRNA delivery to the lung epithelium. Mol Pharm. 2014;11:1808–22.
Ambardekar VV, Han H-Y, Varney ML, Vinogradov SV, Singh RK, Vetro JA. The modification of siRNA with 3′ cholesterol to increase nuclease protection and suppression of native mRNA by select siRNA Polyplexes. Biomaterials. 2011;32:1404–11.
Barnaby SN, Lee A, Mirkin CA. Probing the inherent stability of siRNA immobilized on nanoparticle constructs. Proc Natl Acad Sci U S A. 2014;111:9739–44.
Mokhtarieh AA, Cheong S, Kim S, Chung BH, Lee MK. Asymmetric liposome particles with highly efficient encapsulation of siRNA and without nonspecific cell penetration suitable for target-specific delivery. Biochim Biophys Acta Biomembr. 2012;1818:1633–41.
Yuan F, Dellian M, Fukumura D, Leunig M, Berk DA, Torchilin VP, et al. Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res. 1995;55:3752–6.
Yuan F, Leunig M, Huang SK, Berk DA, Papahadjopoulos D, Jain RK. Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res. 1994;54:3352–6.
Green JJ, Langer R, Anderson DG. A combinatorial polymer library approach yields insight into nonviral gene delivery. Acc Chem Res. 2008;41:749–59.
Dandekar P, Jain R, Keil M, Loretz B, Koch M, Wenz G, et al. Enhanced uptake and siRNA-mediated knockdown of a biologically relevant gene using cyclodextrin polyrotaxane. J Mater Chem B. 2015;3:2590–8.
Park SC, Nam JP, Kim YM, Kim JH, Nah JW, Jang MK. Branched polyethylenimine-grafted-carboxymethyl chitosan copolymer enhances the delivery of pDNA or siRNA in vitro and in vivo. Int J Nanomedicine. 2013;8:3663–77.
Kim TI, Ou M, Lee M, Kim SW. Arginine-grafted bioreducible poly(disulfide amine) for gene delivery systems. Biomaterials. 2009;30:658–64.
Chen L, McCrate JM, Lee JC, Li H. The role of surface charge on the uptake and biocompatibility of hydroxyapatite nanoparticles with osteoblast cells. Nanotechnology. 2011;22:105708.
Kobayashi H, Watanabe R, Choyke PL. Improving conventional enhanced permeability and retention (EPR) effects; what is the appropriate target? Theranostics. 2013;4:81–9.
Nam HY, Nam K, Lee M, Kim SW, Bull DA. Dendrimer type bio-reducible polymer for efficient gene delivery. J Control Release. 2012;160:592–600.
Morris VB, Sharma CP. Enhanced in-vitro transfection and biocompatibility of L-arginine modified oligo (−alkylaminosiloxanes)-graft-polyethylenimine. Biomaterials. 2010;31:8759–69.
Lu S, Morris VB, Labhasetwar V. Codelivery of DNA and siRNA via arginine-rich PEI-based polyplexes. Mol Pharm. 2015;12:621–9.
Savic R, Luo L, Eisenberg A, Maysinger D. Micellar nanocontainers distribute to defined cytoplasmic organelles. Science (New York, NY). 2003;300:615–8.
Gridelli C, Maione P, Rossi A. The potential role of mTOR inhibitors in non-small cell lung Cancer. Oncologist. 2008;13:139–47.
Takahashi H, Wang Y, Grainger DW. Device-based local delivery of siRNA against mammalian target of rapamycin (mTOR) in a murine subcutaneous implant model to inhibit fibrous encapsulation. J Control Release. 2010;147:400–7.
You Z, Qian H, Wang C, He B, Yan J, Mao C, et al. Inhibition of DNA nanotube-conjugated mTOR siRNA on the growth of pulmonary arterial smooth muscle cells. Data in Brief. 2015;5:28–34.
Electronic supplementary material
About this article
Cite this article
Gandhi, N.S., Godeshala, S., Koomoa-Lange, DL.T. et al. Bioreducible Poly(Amino Ethers) Based mTOR siRNA Delivery for Lung Cancer. Pharm Res 35, 188 (2018). https://doi.org/10.1007/s11095-018-2460-z
- drug delivery
- lung cancer