Search for: All records

The development of inert, biocompatible chelation methods is required to harness the emerging positron emitting radionuclide⁴⁵Ti for radiopharmaceutical applications. Herein, we evaluate the Ti^(IV)‐coordination chemistry of four catechol‐based, hexacoordinate chelators using synthetic, structural, computational, and radiochemical approaches. The siderophore enterobactin (Ent) and its synthetic mimic TREN‐CAM readily form mononuclear Ti^(IV)species in aqueous solution at neutral pH. Radiolabeling studies reveal that Ent and TREN‐CAM form mononuclear complexes with the short‐lived, positron‐emitting radionuclide⁴⁵Ti^(IV), and do not transchelate to plasma proteins in vitro and exhibit rapid renal clearance in naïve mice. These features guide efforts to target the⁴⁵Ti isotope to prostate cancer tissue through the design, synthesis, and evaluation of Ent‐DUPA, a small molecule conjugate composed of a prostate specific membrane antigen (PSMA) targeting peptide and a monofunctionalized Ent scaffold. The [⁴⁵Ti][Ti(Ent‐DUPA)]²⁻complex forms readily at room temperature. In a tumor xenograft model in mice, selective tumor tissue accumulation (8±5 %,n=5), and low off‐target uptake in other organs is observed. Overall, this work demonstrates targeted imaging with⁴⁵Ti^(IV), provides a foundation for advancing the application of⁴⁵Ti in nuclear medicine, and reveals that Ent can be repurposed as a⁴⁵Ti‐complexing cargo for targeted nuclear imaging applications.

The development of inert, biocompatible chelation methods is required to harness the emerging positron emitting radionuclide⁴⁵Ti for radiopharmaceutical applications. Herein, we evaluate the Ti^(IV)‐coordination chemistry of four catechol‐based, hexacoordinate chelators using synthetic, structural, computational, and radiochemical approaches. The siderophore enterobactin (Ent) and its synthetic mimic TREN‐CAM readily form mononuclear Ti^(IV)species in aqueous solution at neutral pH. Radiolabeling studies reveal that Ent and TREN‐CAM form mononuclear complexes with the short‐lived, positron‐emitting radionuclide⁴⁵Ti^(IV), and do not transchelate to plasma proteins in vitro and exhibit rapid renal clearance in naïve mice. These features guide efforts to target the⁴⁵Ti isotope to prostate cancer tissue through the design, synthesis, and evaluation of Ent‐DUPA, a small molecule conjugate composed of a prostate specific membrane antigen (PSMA) targeting peptide and a monofunctionalized Ent scaffold. The [⁴⁵Ti][Ti(Ent‐DUPA)]²⁻complex forms readily at room temperature. In a tumor xenograft model in mice, selective tumor tissue accumulation (8±5 %,n=5), and low off‐target uptake in other organs is observed. Overall, this work demonstrates targeted imaging with⁴⁵Ti^(IV), provides a foundation for advancing the application of⁴⁵Ti in nuclear medicine, and reveals that Ent can be repurposed as a⁴⁵Ti‐complexing cargo for targeted nuclear imaging applications.

To harness radiometals in clinical settings, a chelator forming a stable complex with the metal of interest and targets the desired pathological site is needed. Toward this goal, we previously reported a unique set of chelators that can stably bind to both large and small metal ions, via a conformational switch. Within this chelator class, py‐macrodipa is particularly promising based on its ability to stably bind several medicinally valuable radiometals including large^132/135La³⁺,²¹³Bi³⁺, and small⁴⁴Sc³⁺. Here, we report a 10‐step organic synthesis of its bifunctional analogue py‐macrodipa‐NCS, which contains an amine‐reactive −NCS group that is amenable for bioconjugation reactions to targeting vectors. The hydrolytic stability of py‐macordipa‐NCS was assessed, revealing a half‐life of 6.0 d in pH 9.0 aqueous buffer. This bifunctional chelator was then conjugated to a prostate‐specific membrane antigen (PSMA)‐binding moiety, yielding the bioconjugate py‐macrodipa‐PSMA, which was subsequently radiolabeled with large^132/135La³⁺and small⁴⁷Sc³⁺, revealing efficient and quantitative complex formation. The resulting radiocomplexes were injected into mice bearing both PSMA‐expressing and PSMA‐non‐expressing tumor xenografts to determine their biodistribution patterns, revealing delivery of both^132/135La³⁺and⁴⁷Sc³⁺to PSMA+ tumor sites. However, partial radiometal dissociation was observed, suggesting that py‐macrodipa‐PSMA needs further structural optimization.

The therapeutic efficacy of photodynamic therapy is limited by the ability of light to penetrate tissues. Due to this limitation, Cerenkov luminescence (CL) from radionuclides has recently been proposed as an alternative light source in a strategy referred to as Cerenkov radiation‐induced therapy (CRIT). Semiconducting polymer nanoparticles (SPNs) have ideal optical properties, such as large absorption cross‐sections and broad absorbance, which can be utilized to harness the relatively weak CL produced by radionuclides. SPNs can be doped with photosensitizers and have ≈100% energy transfer efficiency by multiple energy transfer mechanisms. Herein, an optimized photosensitizer‐doped SPN is investigated as a nanosystem to harness and amplify CL for cancer theranostics. It is found that semiconducting polymers significantly amplify CL energy transfer efficiency. Bimodal positron emission tomography (PET) and optical imaging studies show high tumor uptake and retention of the optimized SPNs when administered intravenously or intratumorally. Lastly, it is found that photosensitizer‐doped SPNs have excellent potential as a cancer theranostics nanosystem in an in vivo tumor therapy study. This study shows that SPNs are ideally suited to harness and amplify CL for cancer theranostics, which may provide a significant advancement for CRIT that are unabated by tissue penetration limits.

Rapid sequestration and prolonged retention of intravenously injected nanoparticles by the liver and spleen (reticuloendothelial system (RES)) presents a major barrier to effective delivery to the target site and hampers clinical translation of nanomedicine. Inspired by biological macromolecular drugs, synthesis of ultrasmall (diameter ≈12–15 nm) porous silica nanoparticles (UPSNs), capable of prolonged plasma half‐life, attenuated RES sequestration, and accelerated hepatobiliary clearance, is reported. The study further investigates the effect of tumor vascularization on uptake and retention of UPSNs in two mouse models of triple negative breast cancer with distinctly different microenvironments. A semimechanistic mathematical model is developed to gain mechanistic insights into the interactions between the UPSNs and the biological entities of interest, specifically the RES. Despite similar systemic pharmacokinetic profiles, UPSNs demonstrate strikingly different tumor responses in the two models. Histopathology confirms the differences in vasculature and stromal status of the two models, and corresponding differences in the microscopic distribution of UPSNs within the tumors. The studies demonstrate the successful application of multidisciplinary and complementary approaches, based on laboratory experimentation and mathematical modeling, to concurrently design optimized nanomaterials, and investigate their complex biological interactions, in order to drive innovation and translation.

The manifestation of acute kidney injury (AKI) is associated with poor patient outcomes, with treatment options limited to hydration or renal replacement therapies. The onset of AKI is often associated with a surfeit of reactive oxygen species. Here, it is shown that selenium‐doped carbon quantum dots (SeCQDs) have broad‐spectrum antioxidant properties and prominent renal accumulation in both healthy and AKI mice. Due to these properties, SeCQDs treat or prevent two clinically relevant cases of AKI induced in murine models by either rhabdomyolysis or cisplatin using only 1 or 50 µg per mouse, respectively. The attenuation of AKI in both models is confirmed by blood serum measurements, kidney tissue staining, and relevant biomarkers. The therapeutic efficacy of SeCQDs exceeds amifostine, a drug approved by the Food and Drug Administration that also acts by scavenging free radicals. The findings indicate that SeCQDs show great potential as a treatment option for AKI and possibly other ROS‐related diseases.

Cerenkov radiation (CR) from radionuclides can act as a built‐in light source for cancer theranostics, opening a new horizon in biomedical applications. However, considerably low tumor‐targeting efficiency of existing radionuclides and radionuclide‐based nanomedicines limits the efficacy of CR‐induced theranostics (CRIT). It remains a challenge to precisely and efficiently supply CR energy to the tumor site. Here, a “missile‐detonation” strategy is reported, in which a high dose of p‐SCN‐Bn‐deferoxamine‐porphyrin‐PEG nanocomplex (Df‐PPN) is first adminstered as a CR energy receiver/missile to passively target to tumor, and then a low dose of the⁸⁹Zr‐labeled Df‐PPN is administrated as a CR energy donor/detonator, which can be visualized and quantified by Cerenkov energy transfer imaging, positron‐emission tomography, and fluorescence imaging. Based on homologous properties, the colocalization of Df‐PPN and⁸⁹Zr‐Df‐PPN in the tumor site is maximized and efficient CR energy transfer is enabled, which maximizes the tumor‐targeted CRIT efficacy in an optimal spatiotemporal setting while also reducing adverse off‐target effects from CRIT. This precise and efficient CRIT strategy causes significant tumor vascular damage and inhibited tumor growth.