In vivo biodistribution of edelfosine-loaded lipid nanoparticles radiolabeled with Technetium-99 m: Comparison of administration routes in mice

Edelfosine (ET) is a potent antitumor agent but causes severe side effects that have limited its use in clinical practice. For this reason, nanoencapsulation in lipid nanoparticles (LNs) is advantageous as it protects from ET side-effects. Interestingly, previous studies showed the efficacy of LNs containing ET in various types of tumor. In this paper, biodistribution studies of nanoencapsulated ET, administered by three routes (oral, intravenous (IV) and intraperitoneal (IP)), were tested in order to select the optimal route of administration. To do this, ET-LNs were labeled with Technetium-99 m (99mTc) and administered by the oral, IV and IP route in mice. IV admin- istration of the radiolabeled LNs led to fast elimination from the blood circulation and increased accumulation in reticulo-endothelial (RES) organs, while their oral administration could not provide any evidence on their bio- distribution since large radiocomplexes were formed in the presence of gastrointestinal fluids. However, when the LNs were administered by the IP route they could access the systemic circulation and provided more constant blood ET-LN levels compared to the IV route. These findings suggest that the IP route can be used to sustain the level of drug in the blood and avoid accumulation in RES organs

Hemocompatibility of gallium-68 labeled iron oxide nanoparticles coated with 2,3-dicarboxypropane-1,1-diphosphonic acid

Dual-modality contrast agents (DMCA), such as radiolabeled magnetic nanoparticles, have attracted significant attention in diagnostic applications due to their potency for the timely and accurate diagnosis of diseases. The hemocompatibility of a candidate DMCA with human blood is essential for the investigation of its application in vivo. In this respect, here we focused on the evaluation of the hemocompatibility of a new DMCA, that is based on iron oxide nanoparticles (i.e. Fe3O4 magnetite), with human red blood cells (RBCs). The specific iron oxide nanoparticles are surface functionalized with 2,3-dicarboxypropane-1,1-diphosphonic acid (-DPD) and radiolabeled with gallium-68 (68Ga), resulting in 68Ga-DPD-Fe3O4. RBCs of five healthy individuals are incubated at room temperature for 120 min without and with 68Ga-DPD-Fe3O4 at concentrations 0.1 and 1.0 mg/ml. Optical microscopy (OM) and atomic force microscopy (AFM) are employed to assess detailed information on the overall morphological and geometrical characteristics of the entire cell at the microscopic (10−6 m) level and on the membrane morphology at the nanoscopic (10−9 m) level. In addition, a standard hematology analyzer (HA) is used to obtain complete blood count information. At the microscopic level, the combined OM, AFM and HA data revealed that the overall shape/size characteristics of RBCs were preserved upon incubation with 68Ga-DPD-Fe3O4. However, at the nanoscopic level, the AFM results revealed two different kinds of local deconstructions of the RBCs membrane, termed holes and ulcer-like abnormalities, that were observed in both the DMCA-free and DMCA-incubated samples. Holes did not exhibit any statistically significant difference upon incubation with the 68Ga-DPD-Fe3O4 DMCA. On the contrary, ulcer-like abnormalities exhibited two statistically significant differences upon incubation with the 68Ga-DPD-Fe3O4 DMCA. First, increased percentage of RBCs having at least one ulcer-like abnormality; in DMCA-incubated samples 78.6 ± 11.6% for CDMCA = 0.1 mg/ml and 80.4 ± 11.1% for CDMCA = 1.0 mg/ml, while in DMCA-free samples 61.2 ± 8.4% prior to and 63.6 ± 13.5% after incubation. Second, increased number of ulcer-like abnormalities per RBC; in DMCA-incubated samples 4.26 ± 0.62 for CDMCA = 0.1 mg/ml and 3.99 ± 0.97 for CDMCA = 1.0 mg/ml, while in DMCA-free samples 2.84 ± 0.54 prior to and 2.98 ± 0.50 after incubation. The combined OM, AFM and HA results prove fair hemocompatibility of the 68Ga-DPD-Fe3O4 DMCA with human RBCs, thus documenting its potential use in imaging applications. © 202

Gastrin-releasing peptide (GRP) analogues for cancer imaging

Small neuropeptides, labeled with gamma- and/or beta-emitting radionuclides, are currently being investigated for their ability to bind to cell-surface receptors, overexpressed in a wide variety of malignant tissues being, thus, potentially useful for radionuclide detection and/or therapy for tumors. Particular attention has been focused on the amphibian peptide, bombesin (BN), and the molecularly related gastrin-releasing peptide (GRP). These peptides act as neurotransmitters and endocrine cancer cell-growth factors on normal tissues as well as on neoplastic cells of various origin. In recent investigations, modification of the native peptide structure has been attempted in order to obtain derivatives, which might easily be labeled with radionuclides. Thus, iodinated (I-125) BN derivatives, as well as Indium (In-111) labeled BN analogs are currently being investigated, presenting satisfactory tumor localization. Also, some new BN analogs containing a 6-carbon linker have been prepared and labeled with Rhenium-188, resulting in positive in vitro binding to prostate cancer cells. More recent studies refer to the Technetium- 99m labeling of BN, performed either directly, after attaching proper technetium-chelating groups onto the BN sequence, or indirectly, by coupling BN to a preformed 99mTc-tagging ligand. Both types of conjugates were found to have a high in vitro affinity for cells with BN receptors, also presenting satisfactory in vivo uptake in experimental tumor models. Pilot clinical studies of a new BN-derived, 99mTclabeled pentadecapeptide indicated significant uptake by breast cancer and invaded lymph nodes, as well as by prostate cancer, small-cell lung carcinoma, gastro-entero-pancreatic tumors, and others, Further studies of this new GRP derivative, as well as of other new BN-like peptides, are intensively performed internationally today. Key words: radiolabeled neuropeptide

Preliminary Evaluation of a 99mTc Labeled Hybrid Nanoparticle Bearing a Cobalt Ferrite Core: In Vivo Biodistribution

Magnetic nanoparticles have become important tools for imaging a wide range of diseases, improving drug delivery and applying hyperthermic treatment. Iron oxide based nanoparticles have been widely examined, unlike cobalt ferrite based ones. Herein, monodisperse and stable CoFe2O4 nanoparticles have been produced, coated and further stabilized using ethyl 12-(hydroxyamino)-12- oxododecanoate, poly(lactic-co-glycolic acid) and bovine serum albumin. The final product, NBRh1, was fully characterized and has been directly radiolabeled with 99mTc using SnCl2 as the reducing agent in high yields. In vitro stability and hyperthermic properties of 99mTc-NBRh1 were encouraging for further application in low frequencies hyperthermia and biomagnetic applications. In vivo evaluation followed after injection in healthy mice. The planar and SPECT imaging data as well as the biodistribution results were in accordance, showing high liver and spleen uptake as expected starting almost immediately after administration. In conclusion the preliminary results for nanoparticles bearing a cobalt ferrite core justify further investigations towards potential hyperthermic applications, drug transportation and liver or spleen imaging