Applications of Graphene and Graphene Oxide in Smart Drug/Gene Delivery: Is the World Still Flat?

Figures & data

Table 1 Advantages and Limitations of Some Remarkable Published Studies About Functionalized Graphene Oxide Nanoparticles

Type of Nanomaterials	Advantages	Limitations	Carriers/ Drug/ Gene	Ref.
GO–FA–βCD	In vitro cytocompatibility In vivo tumor growth inhibition	Needs for immunogenic and pharmacodynamics studies Low stability	DOX	^Citation32
NGO–PEG–RB	pH dependent, suitable for cancer therapy High specificity	Complex synthetic methods Potential inflammatory effect on lung tissue Needs for in vivo study	DOX	^Citation22
ADR–GO	High drug loading capacity Biocompatible pH responsive release	Similarity between free drug and nano-drug in term of cytotoxicity. Needs for in vivo study Potential accumulation of the nanoparticle in spleen	Adriamycin/doxorubicin	^Citation33
GN–CNT–Fe3O4	pH‐dependent drug release Superparamagnetic Efficient uptake by HepG2 cells	Potential accumulation of GN–CNT–Fe3O4 in hepatocyte Needs for in vivo study Possible immunogenicity	5FU	^Citation34
PEI–GO	High transfection efficiency Biocompatible Sequential gene and drug co-delivery	Complex synthetic methods Low water solubility Needs for animal modeling	siRNA, DOX	^Citation35
PEG–GO	Without loss of biological activity Without enzymatic hydrolysis In vitro cytocompatibility	Needs for protein folding study Needs for inflammatory studies Needs for in vivo studies	Proteins ribonuclease A & protein kinase A	^Citation36
Ti–GO–BMP2	Efficient carrier for therapeutic protein BMP2 High specificity	Unfolding of the protein in the presence of Ti Needs for immunogenic and pharmacodynamics studies	BMP2 protein	^Citation37
NGO–PEG–SN38	Delivery of water insoluble anticancer drugs	Needs for in vivo study Possible unwanted generation of protein corona Cell disruption in higher concentration	SN38 (CPT analog)	^Citation14
GO–sulfonic acid	Co-delivery of multiple drugs Remarkably higher toxicity for cancer cells	Needs for in vivo study Possible immunogenicity	DOX & CPT	^Citation38

Abbreviations: PEG, polyethylene glycol; RB, rituxan (CD20+ antibody); DOX, doxorubicin; ADR, adriamycin/doxorubicin (DOX); FA, folic acid; βCD, β cyclodextrin; 5FU, 5-fluorouracil; CNT, carbon nanotubes; BMP2, bone morphogenetic protein-2; Ti, titanium; CPT, camptothecin; PEI, polyethylenimine.

Figure 1 Schematic of (A) cRGD conjugated to chitosan (RC) and (B) RC-GO-Dox nanocarrier.

Note: Copyright ©2014. Elsevier. Reproduced from Wang C, Chen B, Zou M, Cheng G. Cyclic RGD-modified chitosan/graphene oxide polymers for drug delivery and cellular imaging. Colloids and Surfaces B: Biointerfaces. 2014; 122: 332–340.⁶¹

Figure 2 Scheme of TRAIL/DOX-fGO nanoplatform. (A) Main components of TRAIL/DOX-fGO, and (B) Step by step activity of TRAIL/DOX-fGO, from vessel administration to drug release in the cell nucleus.

Note: Copyright ©2015. John Wiley and Sons. Reproduced from Jiang T, Sun W, Zhu Q, et al. Furin‐Mediated Sequential Delivery of Anticancer Cytokine and Small‐Molecule Drug Shuttled by Graphene. Advanced Materials. 2015; 27 (6):1021–1028.⁶³

Figure 3 (A) NGO-SS-mPEG in extracellular environment (low GSH level), (B) it is internalized into the tumor cell (high GSH level), (C) linkage is cleaved, and (D) DOX is released.

Note: Copyright ©2012. John Wiley and Sons. Reproduced from Wen H, Dong C, Dong H, et al. Engineered redox‐responsive PEG detachment mechanism in PEGylated nano‐graphene oxide for intracellular drug delivery. Small. 2012; 8 (5): 760–769.⁸¹

Figure 4 The mechanism of DOX release process in acidic and high GSH level conditions from rGO/QC-PEG and rGO/QC-PEG/Plu-SH.

Note: Copyright ©2013. Elsevier. Reproduced from Al-Nahain A, Lee SY, In I, et al. Triggered pH/redox responsive release of doxorubicin from prepared highly stable graphene with thiol grafted pluronic. Int J Pharm. 2013; 450 (1): 208–217.⁸⁴

Figure 5 (A) rGO-AuNRVe morphology by TEM, (B) Dox release process from rGO-AuNRVe in the cell (Reproduced with permission).

Note: Copyright ©2015. American Chemical Society. Reproduced from Song J, Yang X, Jacobson O, et al. Sequential drug release and enhanced photothermal and photoacoustic effect of hybrid reduced graphene oxide-loaded ultrasmall gold nanorod vesicles for cancer therapy. ACS nano. 2015; 9 (9): 9199–9209.¹¹⁹

Figure 6 (A) Preparation of Dox loaded GOF-Lip-FA nano theranostic system in a schematic view, (B) Targeted cellular uptake of the GOF-Lip-FA nanohybrid and DOX release in cells body (red particles), (C) In vivo biodistribution of the platform by IV injection and cancer cells uptake, and (D) near-infrared 4T1 breast tumor cells death.

Note: Copyright ©2019. American Chemical Society. Reproduced from Prasad R, Yadav AS, Gorain M, et al. Graphene Oxide Supported Liposomes as Red Emissive Theranostics for Phototriggered Tissue Visualization and Tumor Regression. ACS Applied Bio Materials. 2019; 2 (8): 3312–3320.¹⁶⁸

Figure 7 In vivo performance of GOF-Lip-FA nano theranostic platform. (A–C) in vivo 4T1 cancer diagnosis and distribution of nano theranostic systems by near-infrared fluorescence imaging. (D–E) images of the tumor-bearing animal under laser irradiation and tumor size shrinkage shown in dotted circles. (F) Tumor size after different therapeutic paths. (G) The decrease in tumor size after 21 days. (H) near-infrared fluorescence images of tumor regression after various treatments.

Note: Copyright ©2019. American Chemical Society. Reproduced from Prasad R, Yadav AS, Gorain M, et al. Graphene Oxide Supported Liposomes as Red Emissive Theranostics for Phototriggered Tissue Visualization and Tumor Regression. ACS Applied Bio Materials. 2019; 2 (8): 3312–3320.¹⁶⁸

Yang Y, Zhang YM, Chen Y, Zhao D, Chen JT, Liu Y. Construction of a graphene oxide based noncovalent multiple nanosupramolecular assembly as a scaffold for drug delivery. Chem Eur J. 2012;18(14):4208–4215. doi:10.1002/chem.20110344522374621

 PubMed Web of Science ®Google Scholar

Sun X, Liu Z, Welsher K, et al. Nano-graphene oxide for cellular imaging and drug delivery. Nano Res. 2008;1(3):203–212. doi:10.1007/s12274-008-8021-820216934

 PubMed Web of Science ®Google Scholar

Wu J, Y-S W, X-Y Y, et al. Graphene oxide used as a carrier for adriamycin can reverse drug resistance in breast cancer cells. Nanotechnology. 2012;23(35):355101. doi:10.1088/0957-4484/23/35/35510122875697

 PubMed Web of Science ®Google Scholar

Fan X, Jiao G, Gao L, Jin P, Li X. The preparation and drug delivery of a graphene–carbon nanotube–Fe 3 O 4 nanoparticle hybrid. J Mater Chem B. 2013;1(20):2658–2664. doi:10.1039/c3tb00493g32260953

 PubMed Web of Science ®Google Scholar

Zhang L, Lu Z, Zhao Q, Huang J, Shen H, Zhang Z. Enhanced chemotherapy efficacy by sequential delivery of siRNA and anticancer drugs using PEI‐grafted graphene oxide. Small. 2011;7(4):460–464. doi:10.1002/smll.20100152221360803

 PubMed Web of Science ®Google Scholar

Shen H, Liu M, He H, et al. PEGylated graphene oxide-mediated protein delivery for cell function regulation. ACS Appl Mater Interfaces. 2012;4(11):6317–6323. doi:10.1021/am301936723106794

 PubMed Web of Science ®Google Scholar

La WG, Park S, Yoon HH, et al. Delivery of a therapeutic protein for bone regeneration from a substrate coated with graphene oxide. Small. 2013;9(23):4051–4060. doi:10.1002/smll.20130057123839958

 PubMed Web of Science ®Google Scholar

Liu Z, Robinson JT, Sun X, Dai H. PEGylated nanographene oxide for delivery of water-insoluble cancer drugs. J Am Chem Soc. 2008;130(33):10876–10877. doi:10.1021/ja803688x18661992

 PubMed Web of Science ®Google Scholar

Zhang L, Xia J, Zhao Q, Liu L, Zhang Z. Functional graphene oxide as a nanocarrier for controlled loading and targeted delivery of mixed anticancer drugs. Small. 2010;6(4):537–544. doi:10.1002/smll.20090168020033930

 PubMed Web of Science ®Google Scholar

Wang C, Chen B, Zou M, Cheng G. Cyclic RGD-modified chitosan/graphene oxide polymers for drug delivery and cellular imaging. Colloids Surf B Biointerfaces. 2014;122:332–340. doi:10.1016/j.colsurfb.2014.07.01825064484

 PubMed Web of Science ®Google Scholar

Jiang T, Sun W, Zhu Q, et al. Furin‐mediated sequential delivery of anticancer cytokine and small‐molecule drug shuttled by graphene. Adv Mater. 2015;27(6):1021–1028. doi:10.1002/adma.20140449825504623

 PubMed Web of Science ®Google Scholar

Wen H, Dong C, Dong H, et al. Engineered redox‐responsive PEG detachment mechanism in PEGylated nano‐graphene oxide for intracellular drug delivery. Small. 2012;8(5):760–769. doi:10.1002/smll.20110161322228696

 PubMed Web of Science ®Google Scholar

Al-Nahain A, Lee SY, In I, Lee KD, Park SY. Triggered pH/redox responsive release of doxorubicin from prepared highly stable graphene with thiol grafted pluronic. Int J Pharm. 2013;450(1):208–217. doi:10.1016/j.ijpharm.2013.04.05323624082

 PubMedGoogle Scholar

Song J, Yang X, Jacobson O, et al. Sequential drug release and enhanced photothermal and photoacoustic effect of hybrid reduced graphene oxide-loaded ultrasmall gold nanorod vesicles for cancer therapy. ACS Nano. 2015;9(9):9199–9209. doi:10.1021/acsnano.5b0380426308265

 PubMed Web of Science ®Google Scholar

Prasad R, Yadav AS, Gorain M, et al. Graphene oxide supported liposomes as red emissive theranostics for phototriggered tissue visualization and tumor regression. ACS Appl Bio Mater. 2019;2(8):3312–3320. doi:10.1021/acsabm.9b00335

 PubMedGoogle Scholar