Pharmacokinetic limitations of lapatinib (LPT) often result in low patient compliance and premature therapeutic discontinuation. Complex, long-acting formulations of the LPT are also challenging to develop due to the high crystallinity of the drug, limiting its solubility even in lipidic media. This manifests in the low loading of LPT reported for most of the attempted advanced delivery systems, whereas a few high-loading formulations have shown very fast release. In this work, we hypothesized that rich aromatic rings of LPT can be leveraged to form supramolecular π-π interactions with suitable carriers. Functionalized graphene oxide (GO) derivatives, which are finding increasing application in cancer drug delivery, poly(ethylene glycol)-GO (PEG-GO) and L-lactic acid-GO (LA-GO), were selected as carriers because of the potential of GO to form π-π stacking interactions. Bathochromic shifts of around 40 nm of both the absorption maxima of LPT (261 and 294 nm to 301 and 328 nm), along with peak broadening caused by vibronic coupling between drug and carrier, indicated strong π-π interaction in LPT-PEG-GO. In LPT-LA-GO, significant peak disruption with small peak shifts indicated a putatively weaker π-π association. The ID:IG ratio examined by Raman spectroscopy showed a reduction to 0.82 and 0.50 in LPT-PEG-GO and LPT-LA-GO, respectively, from ∼1.30 before drug loading, supporting absorption spectroscopy observations. These underlying interactions translated into loading efficiencies of 48.7% in LPT-PEG-GO and 44.3% in LPT-LA-GO, which are higher than current literature values. Further, LPT-PEG-GO demonstrated 82% zero-order controlled release up to 168 h at pH 5.0 but only 20% release at pH 7.4. In the case of LPT-LA-GO, an initial 48 h higher dissolution rate of LPT was observed, followed by sustained release up to 168 h with almost 78% release at pH 5.0 and 14% release at pH 7.4. In both LPT-PEG-GO and LPT-LA-GO, the LPT release concentration was in the order of 5-15 μM from a 1 mg/mL formulation, showing the dose can be suitably reduced to maintain desired IC50 values on cancer cell lines. Higher cytotoxicity of LPT-PEG-GO and LPT-LA-GO was observed by MTT assay in MDAMB-231 (breast cancer) and HEK293 (noncancerous) cell lines. Percent cell viability was found to be 69 and 72% (in the case of MDAMB-231 cell line), and 94 and 93% (in the case of HEK 293) of control for LPT-PEG-GO and LPT-LA-GO containing 1 μM loaded LPT, respectively. The cytotoxicity effect was corroborated by cellular uptake and apoptosis studies. In conclusion, functionalized GO demonstrates significant improvement in the loading capacity of LPT through supramolecular interactions, while its release profile can be modulated by GO functionalization, presenting a promising delivery system for enhancing the therapeutic efficacy in the treatment of metastatic breast cancer.
Keywords: functionalization; graphene oxide; lapatinib; release profile; π−π stacking.