Folic acid-functionalized graphene oxide nanosheets via plasma etching as a platform to combine NIR anticancer phototherapy and targeted drug delivery

Abstract

PEGylated graphene oxide (GO) has shown potential as NIR converting agent to produce local heat useful in breast cancer therapy, since its suitable photothermal conversion, high stability in physiological fluids, biocompatibility and huge specific surface. GO is an appealing nanomaterial for potential clinical applications combining drug delivery and photothermal therapy in a single nanodevice capable of specifically targeting breast cancer cells. However, native GO sheets have large dimensions (0.5-5 m) such that tumor accumulation after a systemic administration is usually precluded. Herein, we report a step-by-step synthesis of folic acid-functionalized PEGylated GO, henceforth named GO-PEG-Fol, with small size and narrow size distribution (~30±5 nm), and the ability of efficiently converting NIR light into heat. GO-PEG-Fol consists of a nano-GO sheet, obtained by fragmentation of GO by means of non-equilibrium plasma etching, fully functionalized with folic acid-terminated PEG 2000 chains through amidic coupling and azide-alkyne click cycloaddition, which we showed as active targeting agents to selectively recognize breast cancer cells such as MCF7 and MDA-MB-231. The GO-PEG-Fol incorporated a high amount of doxorubicin hydrochloride (Doxo) (> 33%) and behaves as NIR-light-activated heater capable of triggering sudden Doxo delivery inside cancer cells and localized hyperthermia, thus provoking efficient breast cancer death. The cytotoxic effect was found to be selective for breast cancer cells, being the IC 50 up to 12 times lower than that observed for healthy fibroblasts. This work established plasma etching as a cost-effective strategy to get functionalized nano-GO with a smart combination of properties such as small size, good photothermal efficiency and targeted cytotoxic effect, which make it a promising candidate as photothermal agent for the treatment of breast cancer.

Carbon Nanodots as Functional Excipient to Develop Highly Stable and Smart PLGA Nanoparticles Useful in Cancer Theranostics

“…On the contrary, PLGA-CDs20%@IT released only 50% of its payload in 48 h, displaying a prolonged and sustained release capability without hinting at a burst effect. As widely reported in literature, the NIR-triggered photothermal effect of nanoheaters as CDs, allows a faster drug release due to an increase in temperature [ 8 , 35 ]. However, the drug release kinetics of both PLGA-CDs NPs after laser irradiation were comparable to the kinetics obtained by untreated nanoparticles.…”

Functionalization of Metal and Carbon Nanoparticles with Potential in Cancer Theranostics

“…Remarkable features of GO are mainly due to its chemical modification to give rise to nanocomposite materials with a combination of properties owing to various entities such as polymers and metal nanoparticles (i.e., GNPs or SPIONs) [ 15 , 199 , 200 , 201 ]. In fact, on one hand, the functionalization of GO with polar polymers usually avoid the natural tendency of naked GO to aggregate in physiological media due to adsorption of proteins and salting out phenomena [ 25 , 202 , 203 ]. Polymers also reduce its toxicity and hemolytic effect [ 204 , 205 ].…”

“…PEGylation of the GO’s faces by means of epoxy ring opening reactions with heterobifunctional amine-PEG is uncommon, but much more effective than simple coupling with carboxylic acids at the perimeter. For instance, using this approach stable ultrasmall nanosheets of 30 nm length (GO-PEG-Fol) bearing folic acid both on the planar faces and at the perimeter has been obtained [ 25 ]. GO-PEG-Fol consisted of a nano-GO sheet highly functionalized with folic acid-terminated PEG2000 chains through amidic coupling and azide-alkyne click cycloaddition.…”

“…The potential of this multimodal approach is manifold as it offers to simultaneously achieve efficient treatments with an immediate imaging feedback, opening the way to the implementation of highly targeted and innovative patient-tailored therapies that can be customized according to the individual therapeutic response [ 3 , 4 , 5 ]. To fulfill this purpose, several theranostic materials were explored to date, including metallic nanoparticles (e.g., silver, zinc, gold and iron oxide nanoparticles) [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ], carbon nanomaterials (e.g., nanotubes, fullerenes, nanodots and graphene) [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ], rare-earth elements-based structures [ 26 , 27 ] and polymeric assemblies [ 28 , 29 , 30 , 31 ]. Even though unified by the same goal, theranostic nanomaterials can avail of different features that are direct effects of their physical–chemical, optoelectronic, and magnetic properties, as well as the result of the accurate design of the intelligent nanodevice ( Figure 1 ).…”

Carbon Nanodots for On Demand Chemophotothermal Therapy Combination to Elicit Necroptosis: Overcoming Apoptosis Resistance in Breast Cancer Cell Lines

“…With the development of a theranostic, several nanomaterials such as gold nanoparticles, quantum dots, graphene oxide, and polymer-based nanoparticles have been proposed for cancer treatment and diagnosis [6,10,[12][13][14][15][16][17][18][19]. However, the nanomaterials are considered as mere delivery agents and their inherent effects at the cellular level have so far attracted limited attention.…”