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From the classical radiobiology course in a medical physics graduate program, we learned the most important principle in terms of cell behavior under different radiotherapy dose-fractionation schemes: repair, reassortment, reoxygenation, and repopulation (a.k.a. "4 Rs"). Various immunotherapies are now approved for use in cancer patients as not only secondary options to conventional therapies but also as first-line treatment.[7] The impact of these recent developments of cancer immunotherapy in the field of medical physics is inevitable. Biological therapy is a type of therapy that uses substances from living organisms to treat cancer".[16] Based on this definition, immunotherapy is not a physics topic and therefore should not be included in the medical physics curriculum. [Extracted from the article]

Radiolabeled liposomes have been employed as diagnostic tools to monitor in vivo distribution of liposomes in real-time, which helps in optimizing the therapeutic efficacy of the liposomal drug delivery. This work utilizes the platform of [111In]-Liposome as a drug delivery vehicle, encapsulating a novel 18F-labeled carboplatin drug derivative ([18F]-FCP) as a dual-molecular imaging tool as both a radiolabeled drug and radiolabeled carrier. The approach has the potential for clinical translation in individual patients using a dual modal approach of clinically-relevant radionuclides of 18F positron emission tomography (PET) and 111In single photon emission computed tomography (SPECT). [111In]-Liposome was synthesized and evaluated in vivo by biodistribution and SPECT imaging. The [18F]-FCP encapsulated [111In]-Liposome nano-construct was investigated, in vivo, using an optimized dual-tracer PET and SPECT imaging in a nude mouse. The biodistribution data and SPECT imaging showed spleen and liver uptake of [111In]-Liposome and the subsequent clearance of activity with time. Dual-modality imaging of [18F]-FCP encapsulated [111In]-Liposome showed significant uptake in liver and spleen in both PET and SPECT images. Qualitative analysis of SPECT images and quantitative analysis of PET images showed the same pattern of activity during the imaging period and demonstrated the feasibility of dual-tracer imaging of a single dual-labeled nano-construct. [ABSTRACT FROM AUTHOR]

Here we describe a novel strategy to incorporate indium-111 into near infrared (NIR) emitting Cu-In-Se quantum dots (CIS-QDs) to synthesize intrinsically radiolabeled QDs (rQDs), as a quantitative tool for in vivo SPECT/fluorescence imaging. Multidentate zwitterionic polymer ligands were used to functionalize and improve the stability of CIS-rQDs and reduce nonspecific binding with plasma proteins/cell membrane. CIS-rQDs were taken up by colorectal adenocarcinoma (COLO-205) and human epidermoid carcinoma (KB-3-1) cells at low uptake rate (~0.4%, 2 x 105 QDs per cell at 24 h) and reduced nonspecific interaction of zwitterionic CIS-rQDs with cells was observed by fluorescence microscopy. The cytotoxicity of CIS-rQDs was reduced due to the low toxic inorganic composition of QDs and multidentate zwitterionic surface coating. In 5 out of 6 nude mice bearing either COLO-205 or KB-3-1 tumor, both SPECT and fluorescence imaging demonstrated passive localization of CIS-rQDs in the tumor as early as 6 h post-injection. In these mice the passive accumulation of CIS-rQDs in the tumor, due to leaky vasculature, ranged from ~0.3% ID per g to ~4.6% ID per g at 48 h post-injection (from region of interest analysis of SPECT imaging). This intrinsic radio-labeling strategy provides a nanoparticle platform which incorporates imaging and potentially therapeutic radionuclides with retention of fluorescence intensity. It also provides complimentary quantitative data capabilities for both in vivo SPECT imaging and radiotracer ex vivo analysis. [ABSTRACT FROM AUTHOR]

Microfluidics technology has emerged as a powerful tool for the radiosynthesis of positron emission tomography (PET) and single-photon emission computed tomography radiolabeled compounds. In this work, we have exploited a continuous flow microfluidic system (Advion, Inc., USA) for the [18F]-fluorine radiolabeling of the malonic acid derivative, [18F] 2-(5-fluoro-pentyl)-2-methyl malonic acid ([18F]-FPMA), also known as [18F]-ML-10, a radiotracer proposed as a potential apoptosis PET imaging agent. The radiosynthesis was developed using a new tosylated precursor. Radiofluorination was initially optimized by manual synthesis and served as a basis to optimize reaction parameters for the microfluidic radiosynthesis. Under optimized conditions, radio-thin-layer chromatography analysis showed 79% [18F]-fluorine incorporation prior to hydrolysis and purification. Following hydrolysis, the [18F]-FPMA was purified by C18 Sep-Pak, and the final product was analyzed by radio-HPLC (high-performance liquid chromatography). This resulted in a decay-corrected 60% radiochemical yield and ≥98% radiochemical purity. Biodistribution data demonstrated rapid blood clearance with less than 2% of intact [18F]-FPMA radioactivity remaining in the circulation 60 min post-injection. Most organs showed low accumulation of the radiotracer, and radioactivity was predominately cleared through kidneys (95% in 1 h). Radio-HPLC analysis of plasma and urine samples showed a stable radiotracer at least up to 60 min post-injection. [ABSTRACT FROM AUTHOR]

Increasing evidence indicates that reduced intracellular drug accumulation is the parameter most consistently associated with platinum drug resistance, emphasizing the need to directly measure the intratumor drug concentration. In the era of precision medicine and with the advent of powerful imaging and proteomics technologies, there is an opportunity to better understand drug resistance by exploiting these techniques to provide new knowledge on drug-target interactions. Here, we contribute to this endeavor by reporting on the development of an 18 F-labeled carboplatin derivative ( 18 F-FCP) that has the potential to image drug uptake and retention, including intratumoral distribution, by PET. Methods: Fluorinated carboplatin ( 19 F-FCP) was synthesized using 19 F-labeled 2-(5-fluoro-pentyl)-2-methyl malonic acid ( 19 F-FPMA) as the labeling agent to coordinate with the cisplatin-aqua complex. It was then used to treat cell lines and compared with cisplatin and carboplatin at different concentrations. Manual radiosynthesis and characterization of 18 F-FCP were performed using 18 F-FPMA for coordination with the cisplatin-aqua complex. Automated radiosynthesis of 18 F-FCP was optimized on the basis of manual synthesis procedures. The stability of 18 F-FCP was verified using high-performance liquid chromatography. 18 F-FCP was evaluated using ex vivo biodistribution and in vivo PET imaging in non-tumor-bearing animals as well as in KB-3-1 and COLO-205 tumor xenograft-bearing nude mice. Results: In vitro cytotoxicity studies demonstrated that 19 F-FCP has an antitumor activity profile similar to that of the parent drug carboplatin. In vivo plasma and urine stability analysis showed intact 18 F-FCP at 24 h after injection. PET imaging and biodistribution studies showed fast clearance from blood and major accumulation in the kidneys, indicating substantial renal clearance of 18 F-FCP. Using 18 F-FCP PET, we could image and identify the intratumor drug profile. Conclusion: Our results demonstrated that 19 F-FCP, like carboplatin, retains antitumor activity in various cell lines. 18 F-FCP could be a useful imaging tool for measuring the intratumor drug distribution. This strategy of using a new therapeutic carboplatin derivative to quantify and track platinum drugs in tumors using PET has the potential to translate into a clinically useful imaging tool for individual patients., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Radiolabeled liposomes have been employed as diagnostic tools to monitor in vivo distribution of liposomes in real-time, which helps in optimizing the therapeutic efficacy of the liposomal drug delivery. This work utilizes the platform of [ 111 In]-Liposome as a drug delivery vehicle, encapsulating a novel 18 F-labeled carboplatin drug derivative ([ 18 F]-FCP) as a dual-molecular imaging tool as both a radiolabeled drug and radiolabeled carrier. The approach has the potential for clinical translation in individual patients using a dual modal approach of clinically-relevant radionuclides of 18 F positron emission tomography (PET) and 111 In single photon emission computed tomography (SPECT). [ 111 In]-Liposome was synthesized and evaluated in vivo by biodistribution and SPECT imaging. The [ 18 F]-FCP encapsulated [ 111 In]-Liposome nano-construct was investigated, in vivo, using an optimized dual-tracer PET and SPECT imaging in a nude mouse. The biodistribution data and SPECT imaging showed spleen and liver uptake of [ 111 In]-Liposome and the subsequent clearance of activity with time. Dual-modality imaging of [ 18 F]-FCP encapsulated [ 111 In]-Liposome showed significant uptake in liver and spleen in both PET and SPECT images. Qualitative analysis of SPECT images and quantitative analysis of PET images showed the same pattern of activity during the imaging period and demonstrated the feasibility of dual-tracer imaging of a single dual-labeled nano-construct., Competing Interests: The authors declare no conflicts of interest.

Towards the development of iron oxide nanoparticles with intrinsically incorporated radionuclides for dual Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) and more recently of Single Photon Emission Computed Tomography/Magnetic Resonance Imaging (SPECT/MRI), we have developed intrinsically radiolabeled [(59)Fe]-superparamagnetic iron oxide nanoparticles ([(59)Fe]-SPIONs) as a proof of concept for an intrinsic dual probe strategy. (59)Fe was incorporated into Fe3O4 nanoparticle crystal lattice with 92±3% efficiency in thermal decomposition synthesis. Multidentate poly(acrylic acid)-dopamine-poly(ethylene-glycol-2000) (PAA-DOP-PEG) ligands were designed and synthesized based on facile EDC chemistry and utilized to functionalize the [(59)Fe]-SPIONs. The transverse relaxivity of [(59)Fe]-SPIONs (97±3 s(-1)mM(-1)) was characterized and found to be similar to non-radioactive SPIONs (72±10 s(-1)mM(-1)), indicating that (59)Fe incorporation does not alter the SPIONs' MRI contrast properties. [(59)Fe]-SPIONs were used to evaluate the nanoparticle biodistribution by ex vivo gamma counting and MRI. Nude mice (n=15) were injected with [(59)Fe]-SPIONs and imaged at various time points with 7T small animal MRI scanner. Ex vivo biodistribution was evaluated by tissue-based gamma counting. MRI signal contrast qualitatively correlates with the %ID/g of [(59)Fe]-SPIONs, with high contrast in liver (45±6%), medium contrast in kidneys (21±5%), and low contrast in brain (4±6%) at 24 hours. This work demonstrates the synthesis and in vivo application of intrinsically radiolabeled [(59)Fe]-SPIONs for bimodal detection and provides a proof of concept for incorporation of both gamma- and positron-emitting inorganic radionuclides into the core of metal based MRI contrast agent nanoparticles.

Microfluidics technology has emerged as a powerful tool for the radiosynthesis of positron emission tomography (PET) and single-photon emission computed tomography radiolabeled compounds. In this work, we have exploited a continuous flow microfluidic system (Advion, Inc., USA) for the [(18) F]-fluorine radiolabeling of the malonic acid derivative, [(18) F] 2-(5-fluoro-pentyl)-2-methyl malonic acid ([(18) F]-FPMA), also known as [(18) F]-ML-10, a radiotracer proposed as a potential apoptosis PET imaging agent. The radiosynthesis was developed using a new tosylated precursor. Radiofluorination was initially optimized by manual synthesis and served as a basis to optimize reaction parameters for the microfluidic radiosynthesis. Under optimized conditions, radio-thin-layer chromatography analysis showed 79% [(18) F]-fluorine incorporation prior to hydrolysis and purification. Following hydrolysis, the [(18) F]-FPMA was purified by C18 Sep-Pak, and the final product was analyzed by radio-HPLC (high-performance liquid chromatography). This resulted in a decay-corrected 60% radiochemical yield and ≥98% radiochemical purity. Biodistribution data demonstrated rapid blood clearance with less than 2% of intact [(18) F]-FPMA radioactivity remaining in the circulation 60 min post-injection. Most organs showed low accumulation of the radiotracer, and radioactivity was predominately cleared through kidneys (95% in 1 h). Radio-HPLC analysis of plasma and urine samples showed a stable radiotracer at least up to 60 min post-injection., (Copyright © 2013 John Wiley & Sons, Ltd.)

A novel approach was developed to synthesize radioactive quantum dots (r-QDs) thereby enabling both optical and radionuclide signals to be detected from the same intrinsic bimodal probe. This proof-of-concept is exemplified by the incorporation of the radionuclide (109)Cadmium into the core/shell of the nanoparticle. Green and near infrared (NIR) emission intrinsic r-QDs were synthesized and characterized. Zwitterionic and Poly-polyethlene glycol (PEGylated) ligands were synthesized and used to coat r-QDs. Zwitterionic NIR r-QDs (quantum yield = 11%) and PEGylated NIR r-QDs (quantum yield = 14%) with an average size of 13.8 nm and 16.8 nm were obtained respectively. The biodistribution of NIR zwitterionic and PEGylated r-QDs in nude mice was investigated and zwitterionic r-QDs showed longer blood circulation (t(1/2) = 21.4±1.1 hrs) than their PEGylated counterparts (t(1/2) = 6.4±0.5 min). Both zwitterionic and PEGylated r-QDs exhibited progressive accumulation in the liver and spleen, but the magnitude of the accumulation (%ID/g) was about 3-6 fold higher with the PEGylated r-QDs at all the time points. The results demonstrated the feasibility of r-QDs synthesis in quantitative yield and retention of fluorescence following incorporation of radioactivity into the core/shell of the nanoparticle. The gamma signal from the same fluorescent elemental material enabled quantitative and robust pharmacokinetic measurements and how these changed depended on the type of coating ligands used. This strategy for intrinsically radio-labeling the QDs is currently being implemented in our laboratory for the incorporation of other radiometals.