We submit them to unreasonable loads, and expect them to survive our pounding them on hard pavements. We also add insult to injury by squeezing them into fashionable but uncomfortable footwear which does not conform to the shape of the foot. All this means that many professionals make their living caring for our feet. Worldwide many hundreds of thousands of professional people spend most of their working life looking after the foot. They include orthopaedic surgeons, rheumatologists, diabetologists, orthotists and prosthetists, physical therapists, and podiatrists of whom there are at least 15, in the United States of America alone.
In the English language there are two classic books about the foot, both by anatomists. Two particularly noteworthy studies are those performed by Stewart, Harrington, and colleagues [ 18 , 19 ]. By then, liposome technology had witnessed the development and clinical approval of so-called stealth, i.
The first study aimed at establishing the biodistribution pattern of stealth liposomes in 17 patients with solid tumors. The extended circulation time compared to earlier-generation liposomes [ 41 ] was confirmed by scintigraphic imaging. In the second, more detailed study, 15 patients with locally advanced breast cancer, lung cancer, cervix cancer, or squamous cell HNC, or high-grade glioma, were administered Inlabeled PEGylated liposomes, with the aim of obtaining precise information on the pharmacokinetics of these liposomes.
One of the observations made was that of the daily urinary excretion of a small percentage of the injected In, presumably caused by the slow degradation of the liposomes in the tissues. This preliminary observation deserves further investigation. Indeed, beyond measuring liposomal uptake in the tumor, radiolabeling liposomes could provide a means of quantifying the amount of drug released from the liposomes. In the present case, In urinary excretion might be used as a surrogate marker of drug release from the liposomal formulation. Scintigraphy showed a long circulation time of the liposomes and accumulation mostly in the liver and spleen.
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One of the main findings from this trial was that liposomal accumulation in the tumors could be seen for up to a week after administration. EPR heterogeneity: variability of radiolabeled liposome uptake in tumors. Prolonged retention of the radiolabel is seen despite significant clearance of circulating liposomes, as demonstrated by disappearance of the cardiac blood pool image.
The second lesson was a remarkably large variability of liposome uptake observed in the tumors, even after accounting for tumor size. In contrast, uptake in the main organs liver, spleen, lungs, kidneys was rather uniform between different patients. Although no data were available to explain this heterogeneity, variability in tumor vascularization and local inflammation were proposed as plausible explanations, based on preclinical and other clinical studies.
The use of radiolabeled liposomes to predict drug uptake in patients, in other terms patient stratification, was proposed by the authors as a way to improve response rates in phase II clinical studies. A common feature of the studies described above is that the liposomes contained no other cargo than the radiotracer. The first clinical studies of radiolabeled liposomes containing a therapeutic drug were published in and by Koukourakis et al. In the NSCLC patients, liposomal uptake in the tumors correlated with the degree of tumor micro-vascularization, showing the presence of the EPR effect.
The second study describes the same experiment in seven patients presenting locally advanced sarcomas [ 21 ] Fig. The apparent absence of liposomal drug-related toxicity and the high response rate 4 complete responses out of 7 patients were considered encouraging, despite the low number of subjects and the absence of a control group. Although no measurement of doxorubicin levels by either imaging or biopsy was described, scintigraphy showed accumulation of Tcm at tumor sites previously determined by CT or bone scans, on average 2. This again demonstrates the increased uptake of liposomes in tumors in humans.
Adapted with permission from Koukourakis et al. More recently, Giovinazzo et al. TSC and other Tcm-labeled colloids are clinically approved and routinely used for lymphoscintigraphy and staging of cancers [ 42 ]. After finding a positive correlation between blood levels of TSC and encapsulated doxorubicin, the authors derived a formula to estimate doxorubicin levels in the hands based on TSC measures only.
This estimated value positively correlated with clinical grades of PPE severity. The main advantage of this indirect approach is that it is based on a clinically approved product and could potentially be used as a general predictor of uptake for nanomedicines that are cleared through the MPS. On the other hand, it would still require initial correlation studies to be undertaken for each nanomedicine, whereas radiolabeling of the therapeutic nanomedicine directly and specifically informs on the uptake of the drug.
In an interesting departure from cancer studies, Dams et al. Several interesting findings arose from this study. From a diagnosis perspective, there was excellent concordance between the results from the scans with Tcm-labeled liposomes and Inlabeled IgG, with discordance in only 1 out of 35 patients. The calculated specificity was identical for both methods, and the sensitivity was higher with the liposomes. The liposomes also allowed better delineation of the foci of accumulation than the IgG in some patients, presumably because of the lower rate of reverse diffusion of the liposomes into the blood pool.
It should be noted that the suspected foci were predominantly musculoskeletal and the radiolabeled liposomes failed to detect the single case of endocarditis in the study, highlighting a limitation of this approach. Although the concordance study required the use of a shorter-lived isotope for the first scan to allow a second scan as quickly as possible, one might consider the use of a longer-lived isotope in future studies.
This would allow scanning the patient later, potentially improving the signal-to-background ratio and thereby facilitating diagnosis.
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Later scans may also allow monitoring the response to treatment. Alternatively, modifications of the physico-chemical properties of the liposomes might allow faster clearance from the circulation for more rapid increases in target-to-background ratios, resulting in earlier diagnosis. The authors considered radiolabeled liposomes as a diagnostics tool for detecting infectious or inflammatory foci. In view of the good performance of the Tcm-labeled PEG liposomes in detecting such foci, it is clear that radiolabeled liposomes could also be used as theranostic agents by loading them with antibiotics or anti-inflammatory drugs.
This is particularly true for antibiotics because sub-optimal drug concentrations at the site of infection can lead to the appearance of bacterial resistance.
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Radiolabeled liposomes could help estimate the amount of antibiotic reaching the infectious foci and allow rapid adjustments of the therapeutic schedule. An example of the aforementioned approach is given in a study by Weers et al. In this case, using aerosolized liposomes was intended to provide a slow-release formulation, reducing dosing frequency, to increase drug penetration through the bacterial biofilm and to reduce systemic exposure to the drug.
It also clearly showed the mucociliary escalator in action, with a large fraction of the deposited dose ending up in the stomach after being cleared upwards from the airways and swallowed. An earlier study of radiolabeled nebulized liposomes had also shown longer retention of the liposome-encapsulated tracer [ 26 ]. Bhavna et al. The hypothesis was that a reduced particle size would lead to improved drug delivery by increasing deposition in the peripheral lung alveoli and reducing uptake by alveolar macrophages.
Despite intense research efforts in nanomedicines for drug delivery to the lungs [ 44 ], very few clinical trials appear to have made use of the possibilities offered by non-invasive imaging techniques. This pair of coincident gamma photons is detected by the PET camera, in which detectors are arranged in several static rings, providing 3D images. Despite these advantages, only two recent clinical studies of nanomedicines using PET have had results published as of April , both in the field of oncology. MM is targeted towards HER-2 with the objective of increasing delivery of doxorubicin in HER2-overexpressing cells rather than in macrophages, as observed in a preclinical study [ 45 ].
The authors sought to determine whether the amount of drug reaching the metastases would correlate with therapeutic efficacy.
Treatment with MM was given along with trastuzumab a clinically approved anti-HER2 monoclonal antibody. Results from PET imaging Fig. The regions of interest used to measure tumor deposition of [ 64 Cu]-MM are shown in blue or turquoise outlines. The authors state that free Cu was not detectable in the patients selected for more detailed analysis. This is not surprising, because free Cu has high affinity for liver and spleen tissues and rapidly accumulates in these organs [ 47 ].
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Based on preclinical data showing that the biodistribution of MM could be affected by treatment with cyclophosphamide, the patients selected for the imaging study were taken both from a group receiving MM and trastuzumab and from a group receiving cyclophosphamide in addition. However, no differences in drug uptake were observed between these two groups, leading the patients to be analyzed as a single group for the rest of the study.
There were several important results from the study. The first is the large heterogeneity in drug uptake not only between subjects but also between lesions within subjects. This high variability of the EPR effect is particularly important from a therapeutic point of view, since metastases exposed to insufficient drug concentrations could serve as starting points for further dissemination of cancer cells, potentially negating the initial benefits of the treatment. This led the authors to stratify the patients according to the amount of nanomedicine present in the lesion with the lowest uptake.
Although the study was underpowered to show a correlation between MM uptake and progression-free survival, an encouraging trend was observed that would warrant the enrollment of additional patients. A second lesson was the good agreement between clinical and preclinical data, both in overall nanomedicine distribution and in drug concentrations in the tumors.
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This should strengthen the case for clinical trials when imaging-based preclinical data are encouraging. Furthermore, the authors found no correlation between drug concentrations at the tumors and either drug concentrations in the blood or tumor size. This means that blood sampling will not be predictive of efficacy and highlights the added value of quantitative whole-body imaging techniques.
A limitation of this study may paradoxically reside in the use of Cu as an imaging agent. The other clinical study of a PET-radiolabeled nanomedicine was conducted by Phillips et al. The nanoparticles were also conjugated to an integrin-targeting peptide and engineered to promote renal clearance, and were therefore expected to have a distinct biodistribution pattern compared to liposomal nanomedicines.
This is an interesting feature compared to liposomal nanomedicines, where liver and spleen accumulation complicates the visualization of nearby tumors. This favorable pharmacokinetic profile may enable faster clinical decisions. On the other hand, the nanoparticles were observed to accumulate in the renal cortices of a patient known to have chemotherapy-induced kidney inflammation, potentially complicating the differentiation between tumor areas and inflammatory lesions.
There would be no reason to expect off-tumor inflammation in preclinical models of cancer, and therefore such a chance observation could only be made in a clinical study. This shows the value of incorporating whole-body imaging at the earliest opportunity in clinical studies of nanomedicines.
Furthermore, the combination with an optical probe is an excellent choice for clinical applications of multimodal imaging, allowing tumor localization by PET to be followed by fluorescence-guided surgery for improved tumor resection, ultimately resulting in improved patient outcomes. In magnetic resonance imaging, the subject is placed in a powerful magnetic field, which will align magnetically active nuclei most commonly hydrogen from water molecules either parallel or anti-parallel to the magnetic field.
The small difference in the number of nuclei aligning in each direction gives rise to the magnetic resonance imaging MRI signal. A pulsed radiofrequency can then be used to temporarily disturb the alignments of the nuclei, and the relaxation time back to the original position is measured.