Nanotechnology is the study, design, creation, synthesis, manipulation and application of functional materials, devices, and systems through the control of matter at the nanometre scale. Nanomedicine is the monitoring, repair, construction and control of human biological systems at the molecular level, using engineered nanodevices and nanostructures. Several recent reports have suggested that nanotechnology and nanomedicine will have a significant impact on urological research and clinical practice, allowing urologists to intervene at the cellular and molecular level [1,2]. In this comment we present an update on the use of nanotechnology in the minimally invasive diagnosis and detection, and its role in the treatment of prostate cancer.
As in other fields of surgical oncology, nanotechnology has been used for the detection and diagnosis of urological cancer, in particular prostate cancer. There are many publications on the use of nanotests as tools to measure PSA. Using microcantilevers, which can be thought of as flexible beams, resembling a row of diving boards that can be coated with molecules capable of binding biomarkers, quantification of PSA at clinically significant concentrations was reported . In 2002, the use of a PSA ‘blotting paper’ nanotest assay was reported, and there was a good correlation between the novel test and conventional PSA testing . However, the reliability decreased inversely with the PSA value. Subsequently, a novel reagent consisting of gold nanoparticles and using biolyte-selective surface-enhanced Raman scattering responses detected free PSA levels of ≈1 pg/mL in human serum . Further work showed that after recrystallization of the bacterial cell-surface layer fusion protein on gold chips pre-coated with thiolated secondary cell-wall polymer, a monomolecular protein lattice has been exploited as a sensing layer in surface plasmon resonance biochips to detect PSA . More recently Shulga et al. developed a new spectrophotometric method using covalently attached capture antibody labelled with alkaline phosphatase for the detection of free PSA, and Briman et al. described the production and use of a novel electronic device architecture for the quantitative detection and measurement of PSA. Telomerase activity, which is often increased in malignancy, has also been investigated using nanoparticles that switch on their magnetic state by annealing with telomerase-synthesized TTAGGG sequences, which can then be detected by bench-top magnetic resonance relaxometers. In their study, Grimm et al. stated that these nanoparticles were biocompatible and might be able to detect molecular lesions in vivo.
The mainstay of nanotechnology applications in imaging is the ability to confer in vivo localization and external detectability with high sensitivity and specificity. Angiogenesis in animal models using MRI and nanoparticles targeted to the avb3-integrin has been reported . Furthermore, quantum dots, which are fluorescent semiconductor nanocrystals, have been shown to have possible applications in biomolecular and cellular imaging . Although hydrophobic and toxic properties have until recently limited their use in vivo, by altering the surface structure and limiting the use of toxic semiconductors, such as selenium and cadmium, clinical potential might become a reality. Finally ‘intelligent probes’ have been studied to detect malignant lesions by examining the signature nanostructures and analysing physical properties of prostate tissue, such as electrical conductance, pH, oxygen content, carbon dioxide content and temperature changes .
Methods for staging prostate cancers have improved with the advent of gadolinium- and iron oxide-based nanotechnology for over 5 years. However, the clinical uptake of these imaging techniques has been slow. The technique relies on extravasation of ultra-small supermagnetic iron oxide nanoparticles into the interstitial space and uptake by macrophages in lymph nodes. Harisinghani et al. reported complete detection of patients with positive lymph nodes before radical prostatectomy, compared with only 45% using current size criteria on unenhanced MRI scans alone. Further approaches have used dendritic nanoparticles, which have multiple arms that can complex with targeting moieties, such as antibodies or enzyme substrates, permitting both magnetic and optical detection properties. Sentinel lymph nodes have been mapped using intraprostatic injections of nanocolloid and lymph node scintigraphy. In a recent study, Warncke et al. showed that the location of lymph nodes was highly variable and included the common iliac artery (16%), external iliac artery (33%), internal iliac artery (19%), obturator fossa (26%), presacral region (1%), inguinal fossa or lacuna vasorum (1%), and para aortic region (4%). That report concluded that the lymphatic drainage of the prostate might be more extensive than previously described, and hence further work is needed to verify these findings.
Ironically, many urologists will encounter nanotechnology daily, as nanotechnology treatment of prostate cancer is well established in the form of sustained release of the GnRH analogue leuprorelin-conjugated poly(lactic-coglycolic acid) liposome microspheres in metastatic prostate cancer. However, more contemporary research approaches are concentrating on energy delivery to the prostate using targeted nanotechnology or using nanoparticles to deliver chemotherapeutic agents specifically to prostate cancer within the gland. Kam et al. used near-infrared light at 700–1100 nm to optically stimulate single-walled carbon nanotubes (SWNTs). The transparency of biological tissues to this wavelength of light and the strong absorption of SWNTs in this spectrum, make SWNTs uniquely suited to the delivery of olignucleotides. In addition, near-infrared targeting can cause localized heating of the SWNTs to cause cell destruction in vitro. Folate labelling has further enabled the internalization of nanotubes into folate receptor-expressing cancer cells rather than the folate receptor-negative benign tissue. These SWNTs have been shown to have limited cytotoxicity when used in vitro. More recently, Johanssen et al. investigated the use of magnetic nanoparticles to heat prostatic tissue in an alternating-current magnetic-field applicator. Invasive thermometry was used to monitor heating to 39.4–48.5 °C. This novel interstitial treatment was applied for six weekly hyperthermia sessions of 60 min duration. Several interesting concepts can be extrapolated from this investigation. Injected nanoparticles remained within the prostate for the 6-week treatment duration and could be detected on CT, to ensure adequate prostate distribution with rectal and urethral sparing. In addition, the authors initiated the first clinical application of interstitial hyperthermia with magnetic nanoparticles in a phase I study to evaluate the treatment of local recurrence after radiotherapy with curative intent. Finally, as the folate receptor is often over-expressed in a multitude of cancers, folate receptor-mediated drug delivery is therefore an attractive option to target cancer cells rather than benign folate-receptor negative cells, and the effectiveness of folate-linked, lipid-based nanoparticles as a vector for DNA transfection and for suicide gene therapy to treat prostate cancer, has been reported . Further progress has been made in manufacturing nanoparticles with an oleic acid shell that can be loaded with hydrophobic drugs for the sustained release of chemotherapy. In vitro, these approaches have shown dose-dependent antiproliferative effects compared to controls. This vehicle can also be labelled with antibodies for use in imaging . In prostate cancer cell lines, polypropylenimine dendrimers have been used to deliver c-myc triplex-forming oligonucleotides to inhibit transcription of this oncogene in vitro. These 130–280 nm nanoparticles caused a 65% decrease in c-myc expression, making them useful candidates for gene transfer in malignancy. Finally, in vitro targeting of synthesized antibody against prostate-specific membrane antigen with conjugated dendrimer nanoparticles has also been shown to be a suitable platform for targeted molecule delivery into appropriate antigen-expressing cells . This approach could target cancer cells specifically and spare noncancerous normal cells.
With regards surgical treatment itself, the EnsealTM (Surgrx, Redwood City, CA, USA) device has been used in laparoscopic radical retropubic prostatectomy to seal the dorsal venous complex. Using millions of nanoparticles embedded into the instrument, the temperature regulation of the bipolar diathermy can be optimally controlled, minimizing collateral thermal spread and tissue damage, with effective sealing of vessels up to 7 mm in diameter. The safe use of the Enseal system has been reported in sealing the dorsal venous complex during robot-assisted laparoscopic prostatectomy .
With the introduction of nanodevices, a highly intensive debate can be expected, and indeed, the impact of nanotechnology on human health has been assessed by the Office of Science and Technology in the UK. An independent review raises concerns that nanoparticles, because of their size and ability to pass across cellular membranes, represent a potential biohazard. Stringent attention to safety and exhaustive research into the toxicology of nanoparticles will be mandatory before the widespread clinical use of nanotechnology.
Exciting in vitro and in vivo applications of nanotechnology have been reported in the diagnosis and treatment of prostate cancer, but at least at present, there is a paucity of clinical studies to verify its potential use. As prostate cancer has one of the greatest potentials to benefit from nanotechnology, urologists should be encouraged to actively participate with basic science researchers working in this field. Commencement of phase 1 and phase 2 trials incorporating nanotechnology to evaluate novel diagnostic and therapeutic approaches for the benefit of patients with prostate cancer should be encouraged.