Carbon Nanotubes: Smart Drug/Gene Delivery Carriers

Figures & data

Table 1 Different Medical Applications of CNTs

Application	Description	Ref.
Diagnosis and Imaging
Bio-sensing	CNTs show special optical, mechanical, and electronic properties that make them attractive candidate materials for the manufacture of optical and electrochemical biosensors	[^Citation141]
Bio-imaging	Features such as high photostability and absence of quenching, make CNTs suitable for bio-imaging applications	[^Citation151]
Therapy Applications
Photo-Thermal Therapy	The ability of CNTs to convert near infrared radiation (NIR) into heat is well known	[^Citation152]
Tissue Engineering	CNTs are good materials for tissue engineering due to their biocompatibility, rigidity, mimicking of natural tissue nanofibers, stimulating the adhesion and proliferation of cells and ability to form strong 3D architectures	[^Citation153]
Drug/gene Delivery	CNTs have been considered as carriers for drug/gene delivery due to their high surface area, multifunctional surface chemistry, lack of immunogenicity and unique needle-like shapes with an ability to easily penetrate cell membranes	[^Citation75,^Citation154]
Lab-on-a-chip devices	Lab-on-a-chip (LOC) devices are miniaturized systems in which tiny volumes of fluids flowing in various channels are designed for purposes such as drug screening, cell growth, and disease models. In this regard, CNTs have been used as membrane channels, sensors and channel walls in LOC devices.	[^Citation155]

Table 2 Summary of Articles on CNT Cellular Internalization Mechanisms

Types of Carbon Nanotubes	Length (L)/Diameter (D)	Surface-Modified Complex	Cell Types	Mechanisms	Ref.
SWCNTs	L: >1 µm	Pluronic- F108:CNT	Macrophage cells	Phagocytosis	[^Citation156]
SWCNTs MWCNTs	30–400 nm	–	Murine macrophage RAW264.7 cells	Phagocytosis	[^Citation62]
MWCNT	L: 453.5 ± 6.2	C6-CNTPC	A549 cells	Phagocytosis	[^Citation20]
SWCNTs	L:195–630 nm	–	Murine macrophage cells	Macropinocytosis	[^Citation60]
MWCNTs	L: >300 nm	p(4VP)-MWCNTs	TT1 cells	Macropinocytosis	[^Citation7]
SWCNTs	L: <500 nm/D: 1–2 nm	AO–SWCNTs	Hela cells	Clathrin-mediated endocytosis	[^Citation157]
MWCNTs	L:10 µm/D: 60 nm	–	BEAS-2B cells, HBEpCs	Clathrin- and caveolae-mediated endocytosis	[^Citation158]
SWNTs	L: 0.05–0.2 μm/<1 μm	SWNT-DNA, SWNT- proteins	HeLa cell	Clathrin-dependent endocytosis	[^Citation159]
MWCNTs	D: ~200 nm	Oxidized -MWCNTs	Caco-2 cell	Clathrin-dependent endocytosis	[^Citation160]
CNTs	L: 250–400 nm	PEG-CNT-ABT737 nanodrug	A549 non-small cell lung cancer cells	Clathrin-mediated endocytosis	[^Citation87]
SWNTs	L: 100–200 nm/D: 1–3 nm	FA-SWNTs	HepG2 cells	Folate receptor mediated endocytosis	[^Citation161]
SWNTs	L:50–100 nm/D: 1–3 nm	FA- SWNTs	HepG2 cells	Folate receptor mediated endocytosis	[^Citation162]
MWCNTs	L: 3 lm to 10 lm/D: 50 nm – 300 nm	–	Human neonatal epidermal keratinocytes (HEK)	Lectin receptor mediated endocytic pathway	[^Citation163]
SWCNTs	L: 50–200 nm/D: 1–3 nm	FA-SWCNTs	HepG2 cells	Passive diffusion for 50 nm or less SWNTs Clathrin-mediated endocytosis for 100–200 nm SWNTs	[^Citation164]
MWCNTs	D: 20–30 nm	FITC- MWCNTs	Plant cells	Passive diffusion	[^Citation165]

Abbreviations: HBEpCs, human bronchial epithelial cells; FA, folate acid; C6-CNTPC, coumarin-6 loaded TPGS conjugated MWCNT.

Table 3 Advantages and Disadvantages of Various CNT Cellular Internalization Mechanisms

Mechanism	Positive Characteristics	Negative Characteristics	Ref.
Passive diffusion	Rapid diffusion of CNTs across the cell lipid membrane in a non-invasive manner	Non-specific	[^Citation20]
Phagocytosis	Ability to uptake large particles (~ 1 μm) Specific cell-type targeting	Need a coating on CNTs to enhance recognition and uptake by phagocytes ○ Degradation of cargo by lysosomes	[^Citation15,^Citation166]
Macropinocytosis	Ability to uptake large particles Uptake of cargo through large vacuoles	Non-specific	[^Citation7,^Citation167]
Clathrin-dependent endocytosis	Size-dependent regulation of particle internalization	Degradation of cargo by lysosomes	[^Citation168]
Caveolae-mediated endocytosis	Specific receptors Bypass the endo-lysosomes Enhance the efficiency of transfection	Membrane structure dependent	[^Citation169]

Table 4 Functionalized CNTs and Their Effect on Solubility, Toxicity, and Effective Cellular Internalization Mechanisms

	Functionalized-CNTs	Cell Types	Major Results	Ref.
Solubility	SPAN-MWCNT	–	Weaker π-π bonds between CNTs and SPAN, and high solubility	[^Citation170]
	Pl-PEG-SWCNT	Jurkat cell line	Increase in aqueous solubility by non-covalent functionalization of SWCNTs	[^Citation171]
Cellular uptake	MWCNT-FITC	RAW 264.7 murine macrophages - A459 human lung carcinoma cells	Surface modification of CNTs can facilitate effective cellular uptake The ability of f-CNTs to cross the cell membrane of both cells at a 30–50% internalization rate	[^Citation50]
	Vitamin E TPGS-MWCNT (C6-CNTPC)	A549 cells	Increase in anticancer properties of DTX according to the phagocytosis mechanism of C6-CNTPC	[^Citation20]
	PEGylated CNT-ABT737	A549 non-small cell lung cancer cells	Increase mitochondrial targeting with early endosomal escape, increase accumulation of complex in mitochondria and effective released drug	[^Citation87]
Toxicity	SWCNT-PEG-THFF	D54MG-EGFP cells	This functional group protects D54MG-EGFP cells while the SWCNT backbone is harmful for these cells	[^Citation78]
	CD-SWCNTs	MCF-7 and HeLa cells	Decreases the toxicity of CNTs and adverse side effects as a FMN drug delivery carrier	[^Citation90]
	FA- MWCNTs	HeLa cells	FA- MWCNTs are non-toxic to HeLa cells with cell viabilities more than 90%	[^Citation99]
	CH−β-GP–CNT hybrid hydrogels	3T3 cells	Hydrogels containing CNTs (0.1%) showed no-toxicity in 3T3 cells with high cell viability	[^Citation103]
	SWCNT−PB (SPB)	293T and A549 cells	SPB showed low cytotoxicity to both cell lines and more than an 80% cell viability at a high concentration of 50 μg mL^−1	[^Citation121]
	SWNT-PEG-PEI- AS1411 aptamer	L929 and AGS cells	This functionalized nanoplex showed low cytotoxicity in cells	[^Citation67]
	SWNT-PEI conjugates	N2A murine neuroblastoma cells	None of the SWNT-PEI110, and SWNT-PEI110 carriers had major cytotoxicity except SWNT-acyl-PEI1.8 (S1.8), SWNT-acyl-PEI10 (AC10) and SWNT-acyl-PEI25 (AC25)	[^Citation127]

Abbreviations: Pl-PEG, phospholipid-PEG; FA, folic acid; CH, chitosan; β-GP, β-glycerophosphate; PB, PEI−betaine; SPAN, sulfonated polyaniline; FMN, formononetin.

Figure 1 This scheme shows how DTX was conjugated to MWCNTs.

Notes: Reprinted with permission from Raza K, Kumar D, Kiran C, et al. Conjugation of Docetaxel with Multiwalled Carbon Nanotubes and Codelivery with Piperine: Implications on Pharmacokinetic Profile and Anticancer Activity. Mol Pharm. 2016;13(7):2423–2432. Copyright © 2016 American Chemical Society.⁹³

Figure 2 Schematic illustration of DOX-SPBB-siRNA nanocarriers for treating lung cancer cells.

Notes: Reprinted with permission from Cao Y, Huang HY, Chen LQ, et al. Enhanced Lysosomal Escape of pH-Responsive Polyethylenimine–Betaine Functionalized Carbon Nanotube for the Codelivery of Survivin Small Interfering RNA and Doxorubicin. ACS Appl Mater Interfaces. 2019;11(10):9763–9776. Copyright © (2019) American Chemical Society.¹²¹

Table 5 Other Examples of CNTs Used for the Delivery of Molecules

CNTs	Molecules	Functional Group	Particle Size	Release Control	In vitro/in vivo	Ref.
SWCNTs	Carnosine dipeptide	Modified with PEG at the lysine residues via amide bonds	–	–	–	[^Citation172]
SWNTs	DOX	Modified with oxidative acid and PEG-g-PEI	Diameter 1–2 nm, length 1–3 nm, SSA 380 m^2/g	Acidic pH	In vitro	[^Citation173]
MWCNTs	DOX	Functionalized with (TAT)-chitosan (MWCNTs-TC)	–	–	In vivo, in vitro	[^Citation174]
SWCNT	DTX	Functionalized with iron oxide NPs and coated by PLA co-mPEG micelles	~ 15–50nm	External magnetic fields	In vivo, in vitro	[^Citation175]
SWCNT	EGFP (nEGFP)	Functionalized with streptavidin	~ 200 nm in length	Light-responsive	In vivo, in vitro	[^Citation176]
MWCNT	Zolpidem (ZM)	Modified with D-glucose (Gl)	Diameter of MWCNTCOOH 10 nm, 27 nm in MWCNT-Gl	-	In vitro	[^Citation177]
SWNTs	DOX	Non-covalently functionalized with PL-PEG	~ 1 nm and ~1.2 nm inner and outer diameters, 50–200 nm PEG-coated SWNTs	NIR irradiation	In vitro	[^Citation178]
MWCNT	DTX	Chitosan-folate (CHI-FA) conjugated MWCNT	~ 230 to 483 nm in length	–	In vivo, in vitro	[^Citation179]
MWCNTs	Antigenic protein (OVA)	Modified with lentinan	9–10 nm in diameter, 1–2 μm in length	–	In vivo, in vitro	[^Citation180]

Figure 3 In vivo biodistribution of fluorescent-labeled rCNT (A1 and A2) and fCNT (B1 and B2) in mice.

Notes: Reprinted with permission from Cifuentes-Rius A, Boase NRB, Font I, et al In Vivo Fate of Carbon Nanotubes with Different Physicochemical Properties for Gene Delivery Applications. ACS Appl Mater Interfaces. 2017;9(13):11,461–11,471. Copyright (2017) American Chemical Society.²⁹

Table 6 Cell Viability and in vivo Toxicity Results for Various Concentrations of Functionalized-CNTs

Types of Functionalized CNTs	In vito/in vivo Model	Cell Viability/in vivo Results	Concentration of CNTs (μg/mL)	Ref.
FA- MWCNTs	HeLa cells	>90%	–	[^Citation99]
MWCNT-COOH	HEK 293 cells	91.96/47.78%	25 μg/mL/300 μg/mL	[^Citation181]
MWCNT-COOH	Zebra fish embryos	Non-significant decrease in survival rate	–	[^Citation181]
PLL-CNT@PDA film, PLL-CNT-COOH film	RAW264.7 cells	No viability changes in cells	–	[^Citation148]
SWCNT−PB (SPB)	293T and A549 cells	>80%	50 μg/mL	[^Citation121]
Tangled oxidized multi-walled CNTs (t-ox-MWCNTs)	Wistar strain rat	Low toxicity and long-term biopersistence of the t-ox-MWCNTs in vivo	<100 μg	[^Citation182]
PEGylated SWNT	8–12 to week-old nude mice	Toxicity of high doses was not observed in nude mice	151 mg of PEG-SWNT	[^Citation183]

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