Elucidating the fate of nanoparticles among key cell components of the tumor microenvironment for promoting cancer nanotechnology

Abstract

Successful integration of nanotechnology into the current paradigm of cancer therapy requires proper understanding of the interface between nanoparticles (NPs) and cancer cells, as well as other key components within the tumor microenvironment (TME), such as normal fibroblasts (FBs) and cancer-associated FBs (CAFs). So far, much focus has been on cancer cells, but FBs and CAFs also play a critical role: FBs suppress the tumor growth while CAFs promote it. It is not yet known how NPs interact with FBs and CAFs compared to cancer cells. Hence, our goal was to elucidate the extent of NP uptake, retention, and toxicity in cancer cells, FBs, and CAFs to further understand the fate of NPs in a real tumor-like environment. The outcome of this would guide designing of NP-based delivery systems to fully exploit the TME for a better therapeutic outcome. We used gold nanoparticles as our model NP system due to their numerous applications in cancer therapy, including radiotherapy and chemotherapy. A cervical cancer cell line, HeLa, and a triple-negative breast cancer cell line, MDA-MB-231 were chosen as cancer cell lines. For this study, a clinically feasible 0.2 nM concentration of GNPs was employed. According to our results, the cancer cells and CAFs had over 25-and 10-fold higher NP uptake per unit cell volume compared to FBs, respectively. Further, the cancer cells and CAFs had over 30% higher NP retention compared to FBs. There was no observed significant toxicity due to GNPs in all the cell lines studied. Higher uptake and retention of NPs in cancer cells and CAFs vs FBs is very important in promoting NP-based applications in cancer therapy. Our results show potential in modulating uptake and retention of GNPs among key components of TME, in an effort to develop NP-based strategies to suppress the tumor growth. An ideal NP-based platform would eradicate tumor cells, protect FBs, and deactivate CAFs. Therefore, this study lays a road map to exploit the TME for the advancement of "smart" nanomedicines that would constitute the next generation of cancer therapeutics.

Investigation of Nano-Bio Interactions within a Pancreatic Tumor Microenvironment for the Advancement of Nanomedicine in Cancer Treatment

“…GNP uptake in tumor cells and CAFs were comparable while GNP uptake in NFs was two-fold less compared to that of tumor cells and CAFs. The lower uptake of GNPs in NFs and higher uptake in tumor cells and CAF-98 is consistent with previous studies where CAFs and NFs of melanoma origin were compared to tumor cells of breast and cervical origins [42,43]. Only cells of pancreatic origin were used in this study.…”

“…The retention percentage of GNPs in tumor cells, CAFs, and NFs was approximately the same at 70-80% (Figure 4B). The trend in intracellular retention of NPs is consistent with previous studies where a similar GNP complex was used with different cell lines [42,43]. Typically, GNPs get into the cell via RME where they are caught in endosomes before being fused and localized in lysosomes for handling, and finally exiting the cell through exocytosis where they are excreted via fusion with the cell membrane, as illustrated in Figure 3A.…”

“…A clear reduction in the number of GNPs was apparent in all four cancer cell lines compared to normal media. This could be attributed to two reasons, the first being the redistribution of GNPs from the parent cell to the daughter cells following cell division, and the second reason being the nonequilibrium excretion of GNPs from cells via exocytosis without having enough GNPs getting into the cell due to lack of GNPs in the surrounding media [42]. Even though the number of GNPs in cells 24 h post-incubation with fresh media decreased, tumor cells and CAFs were still able to have more NPs in them compared to NFs (Figure 4A).…”

Combining Gold Nanoparticles with Other Radiosensitizing Agents for Unlocking the Full Potential of Cancer Radiotherapy

“…A recent study shows that the addition of GNPs into current DTX/RT would produce a very promising synergistic therapeutic result [ 92 ]. This smart combination of cancer therapy is proposed to reduce the required dosages, thus minimizing the damage to healthy tissue surrounding the tumor [ 93 ]. GNPs act as a radiosensitizer by boosting local ionizing radiation doses to cancer cells as discussed before.…”

Combination Chemotherapy with Cisplatin and Chloroquine: Effect of Encapsulation in Micelles Formed by Self-Assembling Hybrid Dendritic–Linear–Dendritic Block Copolymers

“…Interestingly, while simultaneous treatment with free drugs had a huge impact on both tumor and non-tumor cells, simultaneous treatment with HDLDBC-bMPA(CQ) or HDLDBC-bGMPA(CQ) and free CDDP resulted in high levels of cytotoxicity only against tumor cells. A possible explanation of this effect could be the reduced ability of Fdh to retain CQ encapsulations compared to tumor cells, as well as changes induced by cisplatin on membrane properties that reduce drug uptake and alter vesicular trafficking [ 62 , 88 , 89 ]. This opens the possibility of safely using the drugs simultaneously to achieve greater tumor cell killing without reducing the concentrations [ 85 , 90 ].…”