Nanostrategies for Therapeutic and Diagnostic Targeting of Gastrin-Releasing Peptide Receptor.

Advances in nanomedicine bring the attention of researchers to the molecular targets that can play a major role in the development of novel therapeutic and diagnostic modalities for cancer management. The choice of a proper molecular target can decide the efficacy of the treatment and endorse the personalized medicine approach. Gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled membrane receptor, well known to be overexpressed in numerous malignancies including pancreatic, prostate, breast, lung, colon, cervical, and gastrointestinal cancers. Therefore, many research groups express a deep interest in targeting GRPR with their nanoformulations. A broad spectrum of the GRPR ligands has been described in the literature, which allows tuning of the properties of the final formulation, particularly in the field of the ligand affinity to the receptor and internalization possibilities. Hereby, the recent advances in the field of applications of various nanoplatforms that are able to reach the GRPR-expressing cells are reviewed.

"To Be or Not to Be" of a Polymer Nanogel-Unravelling the Relationship of Product Properties vs. Synthesis Conditions Governing the Radiation Crosslinking of Poly(acrylic acid) Using GPC/SEC-MALLS.

In this paper, a state-of-the-art multi-detection gel permeation chromatography/size exclusion chromatography (GPC/SEC) system including multi-angle laser light scattering (MALLS) is applied to monitor radiation-induced synthesis of internally crosslinked nanostructures from poly(acrylic acid) (PAA). The aim is to demonstrate that this modern tool yields a more detailed picture of reaction mechanism and product structure than the techniques used to date. The prevailing intramolecular crosslinking narrows the molecular weight distribution from Mw/Mn = 3.0 to 1.6 for internally crosslinked structures. A clear trend from over 0.7 to 0.5 in the Mark-Houwink exponent and a decrease in Rg/Rh from 1.7 to 1.0 point to the formation of nanogels, more rigid and less permeable than the starting coils. Changes in the coil contraction factor (g' = [η]irradiated/[η]linear) as a function of the radical density revealed the existence of two modes in intramolecular crosslinking, the initial one (up to 0.075 radicals per monomer unit) where the compactness of products changes strongly with progressing crosslinking and a second one where further compacting is suppressed by the lower flexibility of the partially crosslinked chain segments. This indicates a transition from soft, still internally crosslinkable nanogels to more rigid structures, less prone to further intramolecular loop formation. Our findings provide means for the tailored design of new PAA nanomaterials.

Towards Cancer Nanoradiopharmaceuticals-Radioisotope Nanocarrier System for Prostate Cancer Theranostics Based on Radiation-Synthesized Polymer Nanogels.

Despite the tremendous development of oncology, prostate cancer remains a debilitating malignancy. One of the most promising approaches to addressing this issue is to exploit the advancements of nanomedicine in combination with well-established nuclear medicine and radiotherapy. Following this idea, we have developed a radioisotope nanocarrier platform of electron-beam-synthesized nanogels based on poly(acrylic acid). We have developed a functionalization protocol, showing the very high (>97%) efficiency of the conjugation in targeting a ligand-bombesin derivative. This engineered peptide can bind gastrin-releasing peptide receptors overexpressed in prostate cancer cells; moreover, it bears a radioisotope-chelating moiety. Our nanoplatform exhibits very promising performance in vitro; the radiolabeled nanocarriers maintained high radiochemical purity of >90% in both the labeling buffer and human serum for up to 14 days. The application of the targeted nanocarrier allowed also effective and specific uptake in PC-3 prostate cancer cells, up to almost 30% after 4 h, which is a statistically significant improvement in comparison to carrier-free radiolabeled peptides. Although our system requires further studies for more promising results in vivo, our study represents a vital advancement in radionanomedicine-one of many steps that will lead to effective therapy for castration-resistant prostate cancer.