*DOI: http://dx.doi.org/10.5772/intechopen.103688 Advances in Graphene Platforms for Drug Delivery in Cancer and Its Biocompatibility*

degradation [18]; and reversal of multidrug resistance (MDR) [19]. These same methodologies have been studied in animal models with good results. For example, in mice/BALBc, GQD platforms can induce apoptosis of tumor cells and have an antitumoral effect [30]. Furthermore, it has been observed that they can eliminate the tumor mass in a subcutaneous mammary tumor model [31].

Messenger ribonucleic acid (mRNA) delivery systems are another type of targeted therapy having a recent boom because of advantages such as biocompatibility and low genotoxicity. Stable graphene platforms functionalized with polyethyleneimine were used in one study, achieving successful delivery of intact mRNA to hepatocarcinoma cells [20]. Let us remember that mRNA has been widely used in the study of gene function and has become popular in the development of new therapeutic strategies for cancer immunotherapy and vaccines. GQDs have also been used as platforms for the delivery of nucleic acids for the regulation of microRNA (miRNAs), negative regulators of gene expression, with great therapeutic effectiveness in HeLa cells [21]. Various investigations indicate that the expression of some miRNAs is altered in some cancers; achieving their regulation would be useful in oncology. And while one would expect targeted cancer therapy to be less toxic than traditional chemotherapy drugs because tumor cells are more dependent on targets than normal cells, this is not the case. Clinical observation indicates that targeted therapies can also produce significant side effects.

Another approach to targeted therapy is for the delivery of enzyme inhibitors to the nucleus. For example, in one study, GQDs were conjugated to imatinib, successfully achieving cytotoxicity and apoptotic cell death in myeloma cells and ovarian cancer cells [22]; imatinib is an inhibitor of the protein tyrosine kinase, which potently and specifically inhibits breakpoint cluster region-Abelson (bcr-abl) tyrosine kinase. However, genetic manipulation and treatments directed at nuclear targets have numerous technical difficulties that are not yet fully resolved. Targeted therapy is complex and does not always work. One of the limitations of this type of therapy is that the drugs for some identified targets are difficult to formulate due to the structure of the target or the way its function is regulated in the cell. An example of this is Ras, a signaling protein that has mutations in up to a quarter of all cancers, but for this type of therapy to work, one would have to know what mutation the gene has [41]. In short, using nanotechnological platforms does not guarantee patient safety, given that side effects of drugs as well as those of the nanomaterial have yet to be assessed.

The lack of response to treatment and the recurrence of initially chemosensitive tumors are responsible for a significant number of deaths in cancer patients. Treatment options used as salvage, such as alternating chemotherapy, dose-escalation, or regional chemotherapy, have yet to yield the expected results. Most cancer patients who initially respond to chemotherapy have relapses because of the so-called acquired resistance to multiple antineoplastic drugs (MDR) [24]. Today, combination therapies seek to address different therapeutic targets using nanobiotechnology. GQD platforms can exhibit all the desirable characteristics of a combination therapy since, as previously mentioned, their surface can be conjugated with different molecules. Their physical, chemical, electrical, and optical properties, however, confer additional functions. As shown, GQDs have a high photothermal modification power under near-infrared radiation (NIR), which allows for their use as photothermal therapy [42–44]. Graphene platforms can also be employed for photodynamic therapy, the goal of which is to generate highly cytotoxic reactive oxygen species (ROS) [45]. A great variety of experimental studies involving different types of cancer have been carried out on animals, in most cases resulting in complete ablation of the tumor [32]. Both photothermic and photodynamic therapy show selectivity toward hyperthermic processes typical of cancer cells, but this is rare with normal cells. GQD platforms with more than one therapeutic effect have been used for the treatment of breast cancer; these include chemothermal therapy [46], chemogenic therapy [23, 47], chemo-photothermal therapy [33], and gene therapy [48]. With these platforms, it has been possible to induce greater cytotoxicity, apoptosis, and reverse drug resistance in breast cancer cells. Moreover, inhibition of tumor growth in an animal model of breast cancer MDA-MB-231 triple-negative has been achieved. Graphene platforms have also been employed as nano radiosensitizers to improve the effectiveness of radiotherapy. Oxidized GOQDs with high phototoxicity has been built to induce a cellular stress response via the production of the reactive oxygen species that would be generated during a tumor's exposure to radiation [49]. Important effects, such as mitochondrial damage and apoptotic death have been observed in colorectal carcinoma cells treated with graphene platforms and radiation therapy [25]. Based on this same principle and thanks to their photodynamic properties, GQDs have also been employed to induce phototoxicity and synergize the cytotoxic effect of radiation in oral squamous cell carcinoma [26].

In addition to these novel uses, GQD platforms are good for the delivery of multiple antineoplastic drugs. A multifunctional platform of GQDs for synergistic breast cancer therapy with controlled release of doxorubicin, methotrexate, and paclitaxel, showed a significant synergistic effect in killing tumor cells with improved efficacy [50]. The advantage of combination therapies is that a therapeutic effect is achieved while reducing drug resistance. On some occasions, however, and as happens in the clinic, the side effects could be considerable. Another method that has been tried for therapeutic efficacy is the conjugation of GQD with a ligand that directs it toward the therapeutic target while additionally carrying the antineoplastic drug. This methodology has been carried out in A549 cells treated with GQDs-biotin-doxorubicin and demonstrates GQDs may have multifunctional effects for cancer treatment [27].

As previously noted, graphene platforms can be built according to the needs of cancer therapy. The construction of ultra-small QDs makes them ideal for achieving not only cell penetration and drug delivery to target sites, but also visualization within the cell. Recently, a graphene platform was used in microspheres with daunorubicin. The small size allowed to monitor drug delivery and the intercalation of daunorubicin in DNA, exerting a better pharmacological effect [28]. Several studies have taken advantage of the fluorescence emitted by QDs to image neoplastic tissues so that, at the same time, drug delivery can be tracked and controlled [51]. In this sense, GQD platforms have become ideal candidates for such purposes due to the high quality of image formation obtained thanks to their fluorescence emission [52]. Additionally, drug/gene delivery in tumor cells has been achieved with greater efficiency both *in vitro* and *in vivo* [53]. For example, GQDs have proved an optimal multifunctional nanocarrier for delivering doxorubicin to specific cancer cells, allowing for the monitoring of intracellular anticancer drug release via imaging and therapeutic efficacy [29, 54, 55]. Ge et al. employed these properties for imaging and the application of dynamic phototherapy for the treatment of breast cancer and induced melanoma in female BALB/c nude mice with favorable results [56]. Other groups have performed functionalization studies of GQDs with silica, hypocrelin A, and porphyria derivatives, managing to obtain multi-color images and antitumor effects in cervical, lung, and breast cancer [57–59]. The results obtained to date appear promising, though they usually depend on the biological variability of the experimental animals.
