Physiological relevance of in-vitro cell-nanoparticle interaction studies as a predictive tool in cancer nanomedicine research.

Cell uptake study is a routine experiment used as a surrogate to predict in vivo response in cancer nanomedicine research. Cell culture conditions should be designed in such a way that it emulates 'real' physiological conditions and avoid artefacts. It is critical to dissect the steps involved in cellular uptake to understand the physical, chemical, and biological factors responsible for particle internalization. The two-dimensional model (2D) of cell culture is overly simplistic to mimic the complexity of cancer tissues that exist in vivo. It cannot simulate the critical tissue-specific properties like cell-cell interaction and cell-extracellular matrix (ECM) interaction and its influences on the temporal and spatial distribution of nanoparticles (NPs). The three dimensional model organization of heterogenous cancer and normal cells with the ECM acts as a formidable barrier to NP penetration and cellular uptake. The three dimensional cell culture (3D) technology is a breakthrough in this direction that can mimic the barrier properties of the tumor microenvironment (TME). Herein, we discuss the physiological factors that should be considered to bridge the translational gap between in and vitro cell culture studies and in-vivo studies in cancer nanomedicine.

Sigma-2 receptor ligand anchored telmisartan loaded nanostructured lipid particles augmented drug delivery, cytotoxicity, apoptosis and cellular uptake in prostate cancer cells.

Recently, the anticancer activity of telmisartan (TEL) has been discovered against prostate cancer. Nevertheless, despite favorable therapeutic profile, poor aqueous solubility and suboptimal oral bioavailability hamper the anticancer efficacy of TEL. Therefore, in this investigation, sigma-2 receptor ligand, 3-(4-cyclohexylpiperazine-1-yl) propyl amine (CPPA) anchored nanostructured lipid particles of telmisartan (CPPA-TEL-NLPs) were engineered using stearic acid for targeting prostate cancer, PC-3 cells. The mean particle size of TEL-NLPs was measured to be 25.4 ± 3.2 nm, significantly (p < 0.05) lower than 32.6 ± 5.3 nm of CPPA-TEL-NLPs. Correspondingly, the zeta-potential of TEL-NLPs was measured to be -15.4 ± 2.3 mV significantly (p < 0.05) higher than -9.6 ± 2.7 mV of CPPA-TEL-NLPs. The encapsulation efficiency of CPPA-TEL-NLPs was estimated to be 72.7 ± 4.3%, significantly (p < 0.05) lower than 77.5 ± 5.4%, displayed by TEL-NLPs. In addition, FT-IR and PXRD confirmed the molecular encapsulation of the drug in amorphous state. In vitro drug release study was conducted to determine the drug delivery potential of tailored nanoparticles. TEL-NLPs released 93.36% of drug significantly (p < 0.05) higher than 85.81%, released by CPPA-TEL-NLPs in 24 h. The IC50 of CPPA-TEL-NLPs was measured to be 20.3 µM significantly (p < 0.05) lower than 36.3 µM presented by TEL-NLPs in PC-3 cells. In contrast, CPPA-TEL-NLPs displayed the IC50 of 41.3 µM, significantly (p > 0.05) not different from 43.4 µM, exhibited by TEL-NLPs in PNT-2 cells. We elucidated that CPPA-TEL-NLPs entered the PC-3 cells via receptor mediated endocytosis pathway and thus exhibited superior cytotoxicity, apoptosis and greater extent of cellular uptake in PC-3 cells. In conclusion, CPPA-TEL-NLPs may be a promising nanomedicine and warrant further in vivo investigations for gaining clinical success.