Positron emission tomography image-guided drug delivery: current status and future perspectives

Abstract

Positron emission tomography (PET) is an important modality in the field of molecular imaging, which is gradually impacting patient care by providing safe, fast, and reliable techniques that help to alter the course of patient care by revealing invasive, de facto procedures to be unnecessary or rendering them obsolete. Also, PET provides a key connection between the molecular mechanisms involved in the pathophysiology of disease and the according targeted therapies. Recently, PET imaging is also gaining ground in the field of drug delivery. Current drug delivery research is focused on developing novel drug delivery systems with emphasis on precise targeting, accurate dose delivery, and minimal toxicity in order to achieve maximum therapeutic efficacy. At the intersection between PET imaging and controlled drug delivery, interest has grown in combining both these paradigms into clinically effective formulations. PET image-guided drug delivery has great potential to revolutionize patient care by in vivo assessment of drug biodistribution and accumulation at the target site and real-time monitoring of the therapeutic outcome. The expected end point of this approach is to provide fundamental support for the optimization of innovative diagnostic and therapeutic strategies that could contribute to emerging concepts in the field of "personalized medicine". This review focuses on the recent developments in PET image-guided drug delivery and discusses intriguing opportunities for future development. The preclinical data reported to date are quite promising, and it is evident that such strategies in cancer management hold promise for clinically translatable advances that can positively impact the overall diagnostic and therapeutic processes and result in enhanced quality of life for cancer patients.

Keywords: cancer; image-guided drug delivery; molecular imaging; personalized medicine; positron emission tomography; theranostics.

Figure 1

PET image-guided tumor targeting using liposome based carrier. PET imaging of brain tumor using PEG-modified liposomes (top panel) and APRPG-modified liposomes (middle panel), labeled with 1-[¹⁸F]fluoro-3,6-dioxatetracosane. The other regions of the brain showed a low background. On the contrary, [¹⁸F]FDG imaged the whole brain, although the accumulation was higher in the tumor region (bottom panel). Autoradiograms shown in the right panel confirmed the region of tumor. Adapted with permission from ref (76). Copyright 2011 Elsevier.

Figure 2

PET image-guided tumor targeting using micelle based carrier. (A) PET imaging of U87 tumor bearing mice at different time points post injection of ⁶⁴Cu-labeled unimolecular micelle loaded with DOX (H40-cRGD-⁶⁴Cu) and ⁶⁴Cu-labeled unimolecular micelle conjugated with cRGD and loaded with DOX (H40-DOX-cRGD-⁶⁴Cu). Adapted with permission from ref (86). Copyright 2012 Elsevier. (B) Ex vivo fluorescence imaging of U87MG tumor, with the excitation and emission set for detecting DOX fluorescence, harvested from mice injected with H40-DOX-⁶⁴Cu or H40-DOX-cRGD-⁶⁴Cu. Adapted with permission from ref (86). Copyright 2012 Elsevier.

Figure 3

PET image-guided tumor targeting using enzyme/prodrug approach. (A) PET imaging using ¹⁸F-FIAU to identify the location, magnitude, and extent of vector-mediated gene expression in gene therapy for recurrent glioblastoma. Treatment responses were recorded by PET imaging with ¹¹C-MET. The region of specific ¹²⁴I-FIAU retention within the tumor after HSV-1-tk-transduction (white arrow) showed the signs of necrosis (cross hairs, right column and reduced methionine uptake [MET]) after ganciclovir treatment. Adapted with permission from ref (98). Copyright 2001 Elsevier. (B) PET imaging of HSV-1-tk activity in tumors after Sindbis/tk infection. Tumor-bearing mice either received no vector treatment (Tumor +, Sindbis/tk −) or received 3 Sindbis/tk treatments via intraperitoneal injection far away from sites of tumor inoculation (Tumor +, Sindbis/tk +). HSV-1-tk activity was determined after intravenous administration of ¹⁸F-FEAU as tracer. Tumors on the right shoulder of SCID mice are indicated by yellow arrows, and white arrows indicate activity in urinary bladder. Adapated with permission from ref (102). Copyright 2006 Society of Nuclear Medicine and Molecular Imaging.

Figure 4

PET image-guided tumor targeting using nanoparticle based carrier. (A) Targeting of integrin α_vβ₃ expression in U87MG tumor bearing mice by gold nanorods (GNR) conjugated with cRGD. PET images at different time points post injection of ⁶⁴Cu-labeled gold nanorods conjugated with DOX (⁶⁴Cu-NOTA-GNR-DOX) and ⁶⁴Cu-labeled gold nanorods conjugated with DOX and cRGD (⁶⁴Cu-NOTA-GNR-DOX-cRGD). Arrowheads indicate the tumors. Adapted with permission from ref (132). Copyright 2012 Ivyspring International Publisher. (B) Targeting of CD105 expression in 4T1 tumor-bearing mice by TRC105-conjugated mesoporous silica nanoparticles. PET images at different time points post injection of ⁶⁴Cu-labeled mesoporous silica (⁶⁴Cu-NOTA-mSiO₂) and ⁶⁴Cu-labeled mesoporous silica conjugated with TRC105 (⁶⁴Cu-NOTA-mSiO₂-TRC105). Tumors were indicated by yellow arrowheads. Adapted with permission from ref (142). Copyright 2013 American Chemical Society. (C) Targeting of lung endothelium in C57BL/6 mice by polymeric nanoparticles conjugated with anti-ICAM antibody. Micro-PET images of mice at different time points post injection of ⁶⁴Cu-labeled nanoparticle conjugated with anti-ICAM antibody (⁶⁴Cu-DOTA-NP-anti-ICAM) and ⁶⁴Cu-labeled nanoparticle conjugated with anti-ICAM antibody after pretreating the mice with lipopolysaccharides (⁶⁴Cu-DOTA-NP-anti-ICAM LPS treated). Adapted with permission from ref (153). Copyright 2008 Society of Nuclear Medicine and Molecular Imaging. (D) Targeting of integrin α_vβ₃-expression in U87MG tumor bearing mice by cRGD-functionalized single walled carbon nanotubes (SWNTs). PET images showing high tumor uptake of SWNT–PEG₅₄₀₀–RGD observed in the U87MG tumor (first row) and control experiment showing blocking of SWNT–PEG₅₄₀₀–RGD tumor uptake by coinjection of free cRGD (second row). The arrows point to the tumors. Adapted with permission from ref (165). Copyright 2007 Nature Publishing Group.

Figure 5

PET image-guided tumor targeting using conventional radiopharmaceuticals. (A) ⁶⁸Ga-DOTATATE PET/CT. (i) Images showing ⁶⁸Ga-DOTATATE avid lesions in T4 vertebral body and 3 metastases in liver (arrow). Physiologic uptake is seen in pituitary, kidneys, bladder, stomach wall, liver, and spleen. (ii) Images from repeated ⁶⁸Ga-DOTATATE PET/CT 1 y later after 3 administrations of ¹⁷⁷Lu-DOTATATE, showing metabolic partial response with reduction in SUV_max of lesion in T4 and liver and no new lesions. Adapted with permission from ref (190). Copyright 2011 Society of Nuclear Medicine and Molecular Imaging. (B) ⁸⁹Zr-trastuzumab PET/CT. (i) A patient with liver and bone metastases, and (ii and iii) two patients with multiple bone metastases. A number of lesions have been specifically indicated by arrows. Adapted with permission from ref (198). Copyright 2010 Nature Publishing Group.