Tumor-tropic Trojan horses: Using mesenchymal stem cells as cellular nanotheranostics

Abstract

Various classes of nanotheranostics have been developed for enhanced tumor imaging and therapy. However, key limitations for a successful use of nanotheranostics include their targeting specificity with limited off-site tissue accumulation as well as their distribution and prolonged retention throughout the entire tumor. Due to their inherent tumor-tropic properties, the use of mesenchymal stem cells (MSCs) as a "Trojan horse" has recently been proposed to deliver nanotheranostics more effectively. This review discusses the current status of "cellular nanotheranostics" for combined (multimodal) imaging and therapy in preclinical cancer models. Emphasis is placed on the limited knowledge of the signaling pathways and molecular mechanisms of MSC tumor-tropism, and how such information may be exploited to engineer MSCs in order to further improve tumor homing and nanotheranostic delivery using image-guided procedures.

Keywords: Cancer; Image-guided therapy; Mesenchymal stem cells; Nanoparticles; Theranostics.

Figure 1

Concept of cellular nanotheranostics following either systemic or intratumoral injection. 1) MSCs are first pre-labeled in vitro with NPs. 2) Labeled MSCs are then injected either systematically or intratumorally. 3) The tumor is imaged using a modality that can detect labeled MSCs in the tumor and off-target sites for making go or no-go decisions on initiating the treatment procedure. 4) When a successful distribution of labeled MSCs is achieved throughout the entire tumor, treatment can be more effective than using “naked” NPs without MSCs.

Figure 2

(A) Biodistribution of i.v. injected “naked” AuNPs and AuNP-labeled MSCs, in which AuNP-labeled MSCs achieved 5.7-fold higher AuNP delivery in the tumor compared to naked AuNPs. cAuNP and PSAuNP stand for control AuNPs and pH-sensitive AuNPs, respectively. Adapted with permission from , copyright 2015 ACS Publications. (B) Distribution of AuNPs post-i.t. injection, where AuNP-labeled NSCs (b, d, f) homogenously delivered AuNPs (dense bright signals) throughout the tumor, in contrast to naked AuNPs that are mostly cleared with some remaining in the center of injection (a, c, e). Adapted from , courtesy of ACS Publications.

Figure 3

Intratumoral distribution profile of theranostic NPs using different delivery routes.

Figure 4

(A) Trans-well pictures and (B) quantitative analysis of migrating MSCs labeled with various concentrations of magnetic nanoparticles (MNPs). MSCs labeled with increasing concentrations of MNPs have enhanced cell migration towards cancer cells. (C) Real-time PCR shows increased CXCR4 expression correlating to higher MNP concentrations used for labeling. Adapted from , courtesy of WILEY.

Figure 5

(A) T2-weighted MRI of co-injected ovarian cancer cells and SPIO-labeled MSCs 14 days post-injection (a, b) and heatmap of subsequent hyperthermia (c). Adapted from , courtesy of Dove Medical Press. (B) T2-weighted MRI of magnetic ternary hybrids complexed with TRAIL (MTN) 24 hours post intracerebral injection of MTN-labeled hMSCs. Yellow arrow indicates signal from labeled MSCs. Adapted from , courtesy of Ivyspring International Publisher. (C) T1-weighted MRI of Gd-containing NP-labeled MSCs 12, 24, and 48 hours post i.v. injection, with accompanying bioluminescence images. Adapted from , courtesy of Nature Springer.

Figure 6

(A) AuNP-labeled MSCs (green) injected i.v. in a U87 brain tumor model are retained up to one-week post-injection. PA images show the presence of blood vessels (red) in the tumor acquired at a wavelength of 532 nm (a) and gold nanocage (AuNC)-labeled hMSCs injected i.v. that homed to the tumor region acquired at a wavelength of 638 nm (b). The images are superimposed in (c) with the inset shown at higher magnification in (d). Adapted from , courtesy of Ivyspring International Publisher. (B) PAI of gold nanostar (AuNS) and AuNS-labeled MSC distribution three days post i.t. injection, showing a 3.3-fold increase in signal area for MSC-mediated delivery. Adapted from , courtesy of Ivyspring International Publisher. (C) PAI of i.t.-injected nanoclusters composed of lipids, doxorubicin, gold nanorods, and iron oxide (LDGI) or LDGI-labeled MSCs, showing a 4.2-fold increase in signal area for MSC-mediated delivery. Adapted , courtesy of WILEY.

Figure 7

(A) Cy5.5-labeled MSCs injected i.v. in a lung carcinoma model, indicating tropism and retention of MSCs within tumors up to 10 days, along with non-specific cell distribution in the liver and spleen. Tumor-free mice were used as control. (B) Ovarian carcinoma model with i.p. injected Cy5.5-labeled MSCs, showing retention of Cy5.5-labeled MSCs within tumors up to 28 days. Tumor-free mice were used as control. Adapted with permission from , copyright 2016 Elsevier.

Figure 8

(A) Temperature changes during irradiation of prostate tumors post-i.t. injection of naked gold nanostars (AuNS) and AuNS-labeled MSCs, showing a differential temperature increase of approximately 2°C for MSC-mediated delivery. Adapted from , courtesy of Ivyspring International Publisher. (B) Temperature changes during irradiation of breast tumors post-i.v. injection of nanoclusters composed of lipids, doxorubicin, gold nanorods, and iron oxide (LDGI), LDGI-labeled MSCs, and LDGI-labeled MSCs, with a differential temperature increase of approximately 13°C for MSC-mediated delivery. Adapted from , courtesy of WILEY. (C) Temperature changes during irradiation of breast tumors post-i.t. injection of gold nanorod-embedded hollow periodic mesoporous organosilica NPs loaded with paclitaxel (AuNR@HPMOs-PTX) and AuNR@HPMO-PTX-labeled MSCs. Adapted with permission from , copyright 2016 ACS Publications.

Figure 9

(A) Survival rates of brain tumor-bearing mice injected i.v. with naked SPIO/paclitaxel (PTX)-loaded polymeric NPs (SPNPs) and SPNP-loaded MSCs, with and without hyperthermia. Adapted with permission from , copyright 2017 Elsevier. (B) Survival rates of ovarian carcinoma-bearing mice injected i.p. with paclitaxel-loaded, DBCO surface functionalized NPs (DBCO-NPs) and DBCO-NP-labeled glycoengineered MSCs. Adapted with permission from , copyright 2016 Elsevier. (C) Relative breast tumor volume of mice injected i.t. with gold nanorod-embedded hollow periodic mesoporous organosilica NPs loaded with paclitaxel (AuNR@HPMOs-PTX) and AuNR@HPMO-PTX-labeled MSCs. Adapted with permission from , copyright 2016 ACS Publications.

Figure 10

(A) Relative brain tumor volumes of mice injected i.t. with MSCs and MSCs labeled with long persistent luminescence NPs complexed with TRAIL (LPLNP-PPT/TRAIL). Adapted with permission from , copyright 2017 WILEY. (B) Luminescence intensity quantification of luciferase-expressing ovarian tumor injected i.p. with recombinant TRAIL protein and magnetic NP-PEI/TRAIL plasmid complexes. Adapted with permission from , copyright 2016 Elsevier. (C, D, and E) Relative tumor size and brain sections stained with Nissl, H&E, and TUNEL for gliomas injected i.v. with herpes simplex virus thymidine kinase (HSV-tk)-transduced MSCs. Ganciclovir (GCV) was administered to kill tumor cells after phosphorylation by HSV-tk. Adapted from , courtesy of Ivyspring International Publisher.

Figure 11

(A) CT images of mice bearing MDA-MB-231 tumors taken 72 hours after each i.v. injection of AuNP-labeled MSCs. Tumors are indicated by blue circles, with red pixels within the circles representing the accumulation of high-density particles at the tumor site. CT images show the accumulation of labeled MSCs in the liver and spleen (white arrows). (B) Treatment outcome in NOD/SCID mice bearing subcutaneous MDA-MB-231 tumors. Adapted from , courtesy of MDPI.