Theranostics and metabolotheranostics for precision medicine in oncology

Abstract

Most diseases, especially cancer, would significantly benefit from precision medicine where treatment is shaped for the individual. The concept of theragnostics or theranostics emerged around 2002 to describe the incorporation of diagnostic assays into the selection of therapy for this purpose. Increasingly, theranostics has been used for strategies that combine noninvasive imaging-based diagnostics with therapy. Within the past decade theranostic imaging has transformed into a rapidly expanding field that is located at the interface of diagnosis and therapy. A critical need in cancer treatment is to minimize damage to normal tissue. Molecular imaging can be applied to identify targets specific to cancer with imaging, design agents against these targets to visualize their delivery, and monitor response to treatment, with the overall purpose of minimizing collateral damage. Genomic and proteomic profiling can provide an extensive 'fingerprint' of each tumor. With this cancer fingerprint, theranostic agents can be designed to personalize treatment for precision medicine of cancer, and minimize damage to normal tissue. Here, for the first time, we have introduced the term 'metabolotheranostics' to describe strategies where disease-based alterations in metabolic pathways detected by MRS are specifically targeted with image-guided delivery platforms to achieve disease-specific therapy. The versatility of MRI and MRS in molecular and functional imaging makes these technologies especially important in theranostic MRI and 'metabolotheranostics'. Our purpose here is to provide insights into the capabilities and applications of this exciting new field in cancer treatment with a focus on MRI and MRS.

Keywords: Cancer; Metabolotheranostics; Precision medicine; Theranostics.

Figure 1

Schematic display of the tumor ecosystem that can be incorporated into strategies for theranostic imaging.

Figure 2

Overview of the strengths of different imaging modalities for structural, functional and molecular imaging, and schematic of a probe used for theranostics.

Figure 3

(A) Structure of a PSMA theranostic agent that carries a prodrug enzyme to convert 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU) that is detected by ¹⁹F MRS and siRNA to downregulate choline kinase (Chk) that results in a decrease of total choline detected by ¹H MRSI. (B) Increased retention of the theranostic agent in a PSMA expressing tumor compared to a non-PSMA expressing tumor. (C) Functional changes in tumor metabolism detected by ¹H MRSI and the formation of the cytotoxic drug 5-FU from 5-FC in the tumor detected by ¹⁹F MRS. Adapted with permission from [21].

Figure 4

Bioorthogonal pretargeting theranostics. (A) Model illustrating the strategy of the target-specific, two-component, two-step drug delivery driven by bioorthogonal trans-cyclooctene (TCO)/tetrazine (Tt) click chemistry in Her-2(+) cancers. Briefly, in this strategy, Her-2(+) cancer cells are prelabeled with TCO conjugated trastuzumab. Drug-loaded albumin conjugated with Tt is delivered subsequently. Multiple click reactions between two components form nanoclusters enhancing the internalization. Adapted with permission from [28]. (B) 3D reconstructed MR images of pretargeted theranostics in tumors showing contrast enhancement in the BT-474 tumor treated with specific mAb and albumin-GdDTPA (right) and control tumor treated with non-reactive components (left). Images were acquired at ~2h after administration of albumin-GdDTPA on a Bruker 9.4T Biospec system using a mouse volume coil and 3D gradient echo T₁-weighted sequence with parameters TE/TR= 2/100ms and RF pulse flip angle of 60-degree.

Figure 5

(A) T₂-weighted MR images subjected to pseudo-color mapping to reveal signal changes in tumor tissues showing signal reduction in blue, corresponding to roughly 4/5, 3/4, and 1/4 of tumor area at 6 h post-contrast with HSP1-, HSP2-, and HSP4-Dex-Fe3O4 nanoparticles, respectively. (B) Histological analyses of H460 tumor tissue specimens acquired 24 h after injection of HSP1-, HSP2-, HSP4-, or Ctrl P-Dex-Fe3O4 nanoparticles. Sections stained with Prussian blue to detect Fe deposition, and counterstained with Nuclear Fast Red. Yellow arrows indicate blood vessels of tumor tissue. (C) Quantification of Prussian blue reaction products from the representative tumor sections. **, P<0.01; * * *, P<0.001 compared with Ctrl P-Dex-Fe3O4 group. Adapted with permission from [31].

Figure 6

(A) schematic illustrations of RGD@AuNPs-Gd99 mTc targeting tumors for theranostics, (B) SPECT/CT imaging of mice bearing H1299 tumors after intravenous injection with the RGD@AuNPs-Gd99 mTc (RGD) probe, (C) T₁-weighted MR imaging of H1299 tumor after intravenous injection with the 29 nm RGD@AuNPs-GdTc (RGD) probe. Adapted with permission from [32].

Figure 7

(A) Representative parametric R2* images (axial slices) of an NSG mouse bearing bilateral flank LS-174T tumors before (pre), 1 h, 6 h, and 24 h post ldbFUS/Fe-NK administration. Yellow outlines show tumor regions of interest. Note that at some imaging time points, left and right tumors were not in the same field of view–thus left & right sides (dashed line) may be from slightly different axial slices. Units in sec⁻¹. (B) Histogram showing relative frequency R2* distributions of whole tumors from (A). The histogram shifts to increasing values of R2* with time in (+)ldbFUS tumor. Adapted with permission from [15].

Figure 8

(A) Schematic illustrations of d-MOFs targeting tumors for combined therapy, loading and delivery of d-MOFs in tumors through EPR effect and pH-responsive degradation of outer MOFs for drug release and dual-modal fluorescence and MRI-guided cancer therapy. (B) T₁-(top) and T₂*-weighted (bottom) in vivo MR images of tumors before, 10 min, 30 min and 24 h after intravenous injection of d-MOFs. T₁-weighted in vivo MR images (coronal planes) of (top) lung circled with dashed line, (middle) liver circled with dashed line, and (bottom) kidney circled with dashed line before, 30 min and 24 h after intravenous injection of d-MOFs. T₂*-weighted in vivo MR images (coronal planes) of (top) lung circled with dashed line, (middle) liver circled with dashed line, and (bottom) tumor circled with dashed line before, 30 min and 24 h after intravenous injection of d-MOFs. Adapted with permission from [44].

Figure 9

(A) Schematic demonstration of CLIO-ICT activation in presence of tumor enzyme MMP-14, to release the active drug, azademethylcolchicine. Azademethylcolchicine targets tubulin to induce apoptosis in tumor cells. (B) Representative T₂-weighted MR images of CLIO-ICT and ferumoxytol at different dilutions. T₂ MSME sequences were used to generate R₂ relaxivities. R₂ relaxivities of CLIO-ICT (blue line) and ferumoxytol (red line). (C) Representative T₂-weighted MR images of mouse brain. Nanoparticle and theranostic nanoparticle delivery is demonstrated by T₂ darkening or negative enhancement in CLIO and CLIO-ICT–treated animals, respectively. On day 14, the tumor periphery is marked by dotted yellow line. (D) Quantification of T₂ darkening. CLIO and CLIO-ICT–treated tumors demonstrated shorter T₂ values corresponding to T₂ darkening or negative enhancement. Adapted with permission from [49].