Review Article

A Review on Characterizations and Biocompatibility of Functionalized Carbon Nanotubes in Drug Delivery Design

Table 1

Some of the recent development with covalent and noncovalent functionalization of CNTs for in vitro drug delivery applications.

CarrierSurface modificationsDrugs/biomolecules/imaging agentsType of bonding  between CNTs  and cargoCell linesRemarksReference

SWCNTs, MWCNTsAcid oxidationSoybean peroxidaseCovalentNontumorigenic human bronchial epithelial cells (BEAS-2B)Acid oxidation increased the number of functional groups and improved CNTs biocompatibility in aqueous environments.[30]

MWCNTsAcid oxidation followed by acylation and subsequently grafted with polyamidoamine (PAMAM) dendrimersCadmium sulfide and silver sulfide quantum dots (QDs) as fluorescence labelling probesCovalentGram-positive bacterium S. aureus and Gram-negative bacteria E. coli and P. aeruginosa The f-MWCNTs-QDs nanohybrids are strong antimicrobial agents against Gram-negative bacteria compared to Gram-positive bacteria.[46]

MWCNTsRefluxed in acid nitric followed by thionyl chloride and then functionalized with PEG diamine Doxorubicin (DOX) and fluorescein isothocyanate (FITC) as fluorescence labelling probesCovalentHuman adenocarcinoma cells (HeLa), human hepatocellular carcinoma cells (HepG2) and human leukemia cells (K562)The PEGylated MWCNTs penetrated into mammalian cells without damage plasma membrane and its accumulation did not affect cell proliferation as well as cell cycle distribution. It was found to accumulate in the multidrug-resistant cancer cells as efficient as in the sensitive cancer cells. [47]

SWCNTsAcid oxidationNoneCovalentMouse fibroblast cells (NIH3T3)The f-SWCNTs were observed mostly accumulated in the cytoplasm, particularly near the mitochondria and in the Golgi bodies and cytoplasmic vacuoles of the f-SWCNTs treated cells.[48]

MWCNTsOxidized in concentrated sulfuric acid/nitric acid mixture and further functionalized with cationic polymer polyethylenimine (PEI) Paclitaxel (PTX), folic acid (FA) as targeting ligand and QDsNoncovalent/covalentHeLa cells and human umbilical vein endothelial cells (HUVEC)The f-MWCNTs-PTX enhanced cytotoxicity capability significantly and exhibited high targeting ability with good aqueous solubility and biocompatibility.[49]

SWCNTsEncapsulated with chitosan (CHI)DOX and FANoncovalentHepatocellular carcinoma cells (SMMC-7721)The obtained f-DOX-FA-CHI-SWCNTs demonstrated high therapeutic payloads and thus, it can kill the cancer cells effectively by releasing DOX at the reduced pH environment. [50]

SWCNTsFunctionalized with carboxylic acid followed by encapsulation with FA-conjugated CHIDOXNoncovalentNoneThe conjugate demonstrated good stability in aqueous medium due to the encapsulation of CHI and exhibited the characteristics of both targeted and controlled release functions.[45]

SWCNTsOxidized in oleum and nitric acid and subsequently functionalized with methoxy (PEG) aminePTXNon-covalentIt was found that the conjugate was not acutely toxic, primarily accumulated in the liver and spleen and proved to be stable and effective both in vitro and in vivo. [51]

MWCNTsPurified using sulfuric acid/nitric acid mixture and further functionalized with polycitric acid-polyethylene glycol-polycitric acid (PCA-PEG-PCA) linear-dendritic copolymersCisplatin (cis-diamminedichloroplatinum) (CDDP)NoncovalentMurine colon adenocarcinoma tumor cancer cells (C26)The synthesized conjugate was able to be introduced into the colon cancer cells and kill the cells effectively.[52]

MWCNTsOxidized in concentrated sulfuric acid and nitric acid, followed by conjugation with iron nanoparticlesDOX and FACovalentHeLa cellsThe DOX/FA-MWCNT@Fe had a sufficient load capacity (32  g/mg) and a prolonged release property assisted by near infrared radiation. It also demonstrated both biologically (active) and magnetically (passive) targeting capabilities toward HeLa cells in vitro with ca. 6-fold higher delivery efficiency of DOX than free DOX.[53]

MWCNTsOxidized in nitric acid and sulfuric acid mixture and subsequently functionalized by 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)-2000] (DSPE-PEG2000-MAL)DOX and angiopep-2 as targeting ligand NoncovalentBrain capillary endothelial cells (BCEC) and glioma cells (C6)The conjugate showed a better anti-glioma effect and a lower cardiac toxicity compared to DOX.[54]

MWCNTs Carboxylation, acylation and followed by amidation process to obtain amine terminated MWCNTsDOX and targeting moiety D- -tocopheryl PEG 1000 succinate (vitamin E TPGS)NoncovalentHuman breast cancer cells (MCF-7) The formulation demonstrated enhanced cytotoxicity and mostly taken up by the cancer cells via endocytosis mechanism. It has longer survival span (44 days) compared to untargeted formulation (23 days) and free DOX (18 days).[55]

Partially carboxylated MWCNTsAcid oxidation in nitric acid 70%Liposomes without PEG-DSPE or drugCovalentHuman fibroblast adherent cells (HEK 293)The system can deliver a large amount of drug into cells and further preventing potential cytotoxicity effects of CNTs when administered at high dosage.[56]

SWCNTsAcid oxidation, acylation and thioamidation processAzithromycin (AZ)CovalentMicrococcus luteus In vitro antibacterial assay of the conjugate confirmed the release of AZ.[34]

MWCNTsAcid oxidation in nitric acid and sulfuric acid mixtureCHI, bovine serum albumin (BSA) and FITCNoncovalentHeLa cellsThe conjugate obtained good stability and dispersity in aqueous solution over 30 days. It is biocompatible with HeLa cells in which the cell viability is 81% after incubation with concentration 100  g mL−1 for 24 h incubation. BSA immobilization efficiency was found to be improved by 0.8 times and cellular toxicity was decreased by 50% compared with carboxylated MWCNTs.[57]

MWCNTsAcid purification in HCl solutionPoly-L-lysine (PLL)NoncovalentNoneThe results showed that the MWCNTs-PLL exhibited good dispersion in water and was found to be pH-dependent.[58]

MWCNTsPoly(acrylic acid) was grafted on MWCNTs through free radical polymerizationDOX, FA and iron oxide magnetic nanoparticlesNoncovalentHuman glioblastoma cells (U87)The system demonstrated enhanced cytotoxicity toward U87 cells compared with free DOX. It was taken up by U87 cells with subsequent intracellular release of DOX, followed by transport of DOX into the nucleus leaving the nanocarrier in the cytoplasm.[59]

MWCNTsFunctionalization with magnetic poly(acrylic acid)Gemcitabine (GEM)NoncovalentHuman pancreatic cancer cells (BxPC-3 and SW1990)The formulation had high anti-tumour activity in vitro compared to free GEM.[60]

SWCNTsAcid oxidation in nitric acid and sulfuric acid mixtureNoneCovalentPrimary human umbilical vein endothelial cells (HUVE)The f-SWCNTs had limited toxicity for HUVE cells in vitro and therefore, it could be used as a potential nanocarrier of antiangiogenic drugs for targeting the vasculature. [61]

SWCNTs, SWCNT-COOHNonePhospholipids (PL) were covalently conjugated to hyaluronan (HA) via amine-coupling chemistry to obtain PL-HA conjugateNoncovalentMurine macrophages (RAW 264.7) and the epithelial colon adenocarcinoma cells (HCT 116)The findings showed that the CNTs-PL-HA internalized into macrophages and exhibited low cytotoxicity. Furthermore, it did not induce pro-inflammatory cytokines or mitochondrial toxicity with leukocytes in contrast to non-modified CNTs. [62]

MWCNTsAcid oxidation in nitric acid and sulfuric acid mixtureCarvedilol (CAR) and PAMAM dendrimersCovalentNonePAMAM-MWCNTs enhanced the drug-loading capacity as well as drug dissolution significantly and, hence, it could be developed as potential nanocarrier for poorly water-soluble drug. [63]

SWCNTsFunctionalization with Sgc8c aptamer (targeting agent) Daunorubicin (Dau) NoncovalentHuman T lymphoblast cells (Molt-4) and human myeloma cells (U266)This tertiary complex was found to be pH-dependent with controlled release function and able to selectively deliver Dau to target Molt-4 cells. [64]

SWCNTsFunctionalization with FANoneNoncovalentHuman monocytic cells (THP-1)The conjugate had low toxicity, good water solubility and was internalized by THP-1 cells.[65]