PEGylated Nanographene Oxide for Delivery of Water-Insoluble Cancer Drugs

Abstract

It is known that many potent, often aromatic drugs are water insoluble, which has hampered their use for disease treatment. In this work, we functionalized nano-graphene oxide (NGO), a novel graphitic material, with branched polyethylene glycol (PEG) to obtain a biocompatible NGO-PEG conjugate stable in various biological solutions, and used them for attaching hydrophobic aromatic molecules including a camptothecin (CPT) analog, SN38 non-covalently via π-π stacking. The resulting NGO-PEG-SN38 complex exhibited excellent water solubility while maintaining its high cancer cell killing potency similar to that of the free SN38 molecules in organic solvents. The efficacy of NGO-PEG-SN38 was far higher than that of irinotecan (CPT-11), a FDA approved water soluble SN38 prodrug used for the treatment of colon cancer. Our results showed that graphene is a novel class of material promising for biological applications including future in vivo cancer treatment with various aromatic, low-solubility drugs.Graphene has emerged as a 2D material with interesting physical properties. 1,2 Intensive research is on-going to investigate the quantum physics in this system and potential applications for nano-electronic devices 2 , transparent conductors and nano-composite materials 3 . Thus far, little has been done to explore graphene in biological systems, despite much effort in the area of carbon nanotubes for in vitro and in vivo biological applications. 4-9 Here, we synthesize and functionalize nanoscale graphene oxide (NGO) sheets (<50nm) by branched, biocompatible polyethylene glycol (PEG) to render high aqueous solubility and stability in physiological solutions including serum. We then uncover a unique ability of graphene in attaching and delivery of aromatic, water insoluble drugs.It is known that clinical use of various potent, hydrophobic molecules (many of them aromatic) is often hampered by their poor water solubility. Although synthesis of water soluble pro-drugs may circumvent the problem, the efficacy of the drug decreases. Here, we show that PEGylated NGO (NGO-PEG) readily complexes with a water insoluble aromatic molecule SN38, a camptothecin (CPT) analog, 10 via non-covalent van der Waals interaction. The NGO-PEG-SN38 complex exhibits excellent aqueous solubility and retains the high potency of free SN38 dissolved in organic solvents. The toxicity exceeds that of irinotecan (CPT-11, a FDA approved SN38 prodrug for colon cancer treatment) by 2-3 orders of magnitude.We prepared graphene oxide by oxidizing graphite using a modified Hummer's method. 3,11 The resulting GO (single layered and few-layered, Supp Info. Fig.S1) was soluble in water but aggregated in solutions rich in salts or proteins such as cell medium and serum (Fig. 1a). This was likely due to screening of the electrostatic charges and non-specific binding of proteins on the GO. 12 To impart aqueous stability and prevent bio-fouling, we sonicated the GO to make them into small pieces and conjugated a 6-armed PEG-amine stars to the carboxylic acid...

Graphene‐Based MicroRNA Transfection Blocks Preosteoclast Fusion to Increase Bone Formation and Vascularization

“…Preparation of GO‐PEI‐miR‐7b and Cell Transfection : GO was prepared by Hummer's method with flake expandable graphite used as the original material as reported 26. For GO‐PEI complexes preparation, PEI solution (1 mg mL −1 ) was slowly added into GO solution (0.1 mg mL −1 ) in 10 min.…”

Graphene/polymer composites for energy applications

“…In this case, the functional groups of polymer chains react with those of graphene sheets to form chemical connects. For example, the carboxylic groups of GO can react with hydroxyl or amine groups of a polymer via esterification 85 or amidation reactions 86,87 to form graphene/polymer composites.…”

Mesoporous carbon biomaterials

“…Of the carbon-family members, sp 2 carbon-based materials such as fullerene [4,5], carbon nanotubes [1,[6][7][8][9][10][11], carbon dots [12][13][14], and graphene [15][16][17][18], have been explored for promising applications in biomedicine, including drug delivery, gene transfection, photothermal therapy, photodynamic therapy, biosensing, and even tissue engineering [19][20][21]. For instance, the hollow space in fullerene/carbon nanotubes and large surface-to-volume ratio of graphene can be used for the encapsulation and intracellular delivery of therapeutic agents.…”