Etioclinical profile and outcome of acute bacterial meningitis in post neo natal U-5 children: a study from tertiary care center of coastal Odisha, India

Background: Acute bacterial meningitis (ABM) continues to remain an important cause of morbidity, mortality and handicap in children despite availability of wide range of antimicrobials. The microorganisms vary according to age, socio economic condition and geographical area along with other factors.Methods: A prospective study was conducted over 2.5 years from October 2012 to April 2015 in the department of pediatrics, SVP Institute of Pediatrics, SCB Medical College, Cuttak, Odisha, India. Total 104 subjects were included after taking meticulous inclusion criteria.Results: Out of 104 cases, majority (70.2%) were infants. 60.6% were male with M:F ratio 1.5:1. Fever was the commonest symptom in 69.2% followed by convulsion 61.5%, vomiting 36.5%, altered sensorium 33.7%. On examination 69.2% children were febrile, having bulging fontanelle in 34.6%, pneumonia 31.7%, positive meningeal sign 29.8%, cranial nerve palsies 14.4%, papilledema 12.5% and hemiplegia 11.5% cases. GCS were poor (100/cumm). In 82 cases (78.8%) etiological agents were identified consisting of H. influenzae in 46.4%, S. pneumoniae in 36.6%, E. coli in 8.6% and others in 8.4%. CT scan of brain revealed brain edema in 29.4% followed by subdural effusion 19.6%, hydrocephalus 17.6% and infarction in 5.9%. 63.5% children were recovered completely. Mortality was 16.3% with sequelae in 20.2% cases.Conclusions: Hib and Pneumococci were two most common organisms causing ABM in U-5 children with high mortality and sequelae which can be prevented by early diagnosis, optimum lab diagnostic facility and mass vaccination. There is urgent need to include Pneumococcal vaccine in NIP for substantial reduction of infant mortality

PSMA-Targeted Nanotheranostics for Imaging and Radiotherapy of Prostate Cancer

Targeted nanotheranostic systems offer significant benefits due to the integration of diagnostic and therapeutic functionality, promoting personalized medicine. In recent years, prostate-specific membrane antigen (PSMA) has emerged as an ideal theranostic target, fueling multiple new drug approvals and changing the standard of care in prostate cancer (PCa). PSMA-targeted nanosystems such as self-assembled nanoparticles (NPs), liposomal structures, water-soluble polymers, dendrimers, and other macromolecules are under development for PCa theranostics due to their multifunctional sensing and therapeutic capabilities. Herein, we discuss the significance and up-to-date development of “PSMA-targeted nanocarrier systems for radioligand imaging and therapy of PCa”. The review also highlights critical parameters for designing nanostructured radiopharmaceuticals for PCa, including radionuclides and their chelators, PSMA-targeting ligands, and the EPR effect. Finally, prospects and potential for clinical translation is discussed

PSMA-Targeted Nanotheranostics for Imaging and Radiotherapy of Prostate Cancer

Targeted nanotheranostic systems offer significant benefits due to the integration of diagnostic and therapeutic functionality, promoting personalized medicine. In recent years, prostate-specific membrane antigen (PSMA) has emerged as an ideal theranostic target, fueling multiple new drug approvals and changing the standard of care in prostate cancer (PCa). PSMA-targeted nanosystems such as self-assembled nanoparticles (NPs), liposomal structures, water-soluble polymers, dendrimers, and other macromolecules are under development for PCa theranostics due to their multifunctional sensing and therapeutic capabilities. Herein, we discuss the significance and up-to-date development of "PSMA-targeted nanocarrier systems for radioligand imaging and therapy of PCa". The review also highlights critical parameters for designing nanostructured radiopharmaceuticals for PCa, including radionuclides and their chelators, PSMA-targeting ligands, and the EPR effect. Finally, prospects and potential for clinical translation is discussed

PSMA-Targeted Nanotheranostics for Imaging and Radiotherapy of Prostate Cancer

Targeted nanotheranostic systems offer significant benefits due to the integration of diagnostic and therapeutic functionality, promoting personalized medicine. In recent years, prostate-specific membrane antigen (PSMA) has emerged as an ideal theranostic target, fueling multiple new drug approvals and changing the standard of care in prostate cancer (PCa). PSMA-targeted nanosystems such as self-assembled nanoparticles (NPs), liposomal structures, water-soluble polymers, dendrimers, and other macromolecules are under development for PCa theranostics due to their multifunctional sensing and therapeutic capabilities. Herein, we discuss the significance and up-to-date development of “PSMA-targeted nanocarrier systems for radioligand imaging and therapy of PCa”. The review also highlights critical parameters for designing nanostructured radiopharmaceuticals for PCa, including radionuclides and their chelators, PSMA-targeting ligands, and the EPR effect. Finally, prospects and potential for clinical translation is discussed

Modulating Early Stage Amyloid Aggregates by Dipeptide-Linked Perylenebisimides: Structure–Activity Relationship, Inhibition of Fibril Formation in Human CSF and Aβ1–40

Amyloid aggregation is observed in many neurodegenerative diseases, but the formation of final plaque seldom correlates to the disease severity. Early and intermediate structures such as soluble oligomers are considered as primary toxic species in protein misfolding diseases specifically linked to Aβ in Alzheimer’s disease (AD). Two peptide-linked perylenebisimide isomers (PAPAP and APPPA) were developed to study the structure–activity relationship with a toxic Aβ oligomer in commercial Aβ as well as in human cerebrospinal fluid (CSF), diminish and inhibit them, and prevent them from forming toxic amyloid fibrils from an early stage. Self-aggregation of perylenebisimides enables the formation of nano/micro-objects that are used to interact with the hydrophobic regions of the peptide and direct the peptide aggregation into an “off-pathway”, preventing mature fibril formation. Remarkably, one of the Ala-Phe dipeptide-linked perylenebisimide isomers (APPPA) showed a high selectivity toward an Aβ oligomer and could also cross the endothelial monolayer barrier (blood–brain barrier, BBB) more efficiently than the other derivative (PAPAP). Kinetic ThT studies and AFM imaging provided strong proof of both of the isomers being able to inhibit fibrillation of prefibrillar and oligomeric Aβ in both the commercial Aβ1–40 peptide as well as in the real human CSF sample. Further, a correlation has been built using pristine fluorescence of perylenebisimides, showing modulation and “oligo-blocking”. The obtained data provides clear evidence that the mutual aggregation between the modulator and amyloid aggregate becomes predominant compared to their individual aggregation. These results reinforce the development of the structural platform design to diminish toxic oligomers, inhibit them, and prevent the formation of toxic amyloid fibrils at an early stage

Prostate-Specific Membrane Antigen Targeted Deep Tumor Penetration of Polymer Nanocarriers.

Tumoral uptake of large-size nanoparticles is mediated by the enhanced permeability and retention (EPR) effect, with variable accumulation and heterogenous tumor tissue penetration depending on the tumor phenotype. The performance of nanocarriers via specific targeting has the potential to improve imaging contrast and therapeutic efficacy in vivo with increased deep tissue penetration. To address this hypothesis, we designed and synthesized prostate cancer-targeting starPEG nanocarriers (40 kDa, 15 nm), [89Zr]PEG-(DFB)3(ACUPA)1 and [89Zr]PEG-(DFB)1(ACUPA)3, with one or three prostate-specific membrane antigen (PSMA)-targeting ACUPA ligands. The in vitro PSMA binding affinity and in vivo pharmacokinetics of the targeted nanocarriers were compared with a nontargeted starPEG, [89Zr]PEG-(DFB)4, in PSMA+ PC3-Pip and PSMA- PC3-Flu cells, and xenografts. Increasing the number of ACUPA ligands improved the in vitro binding affinity of PEG-derived polymers to PC3-Pip cells. While both PSMA-targeted nanocarriers significantly improved tissue penetration in PC3-Pip tumors, the multivalent [89Zr]PEG-(DFB)1(ACUPA)3 showed a remarkably higher PC3-Pip/blood ratio and background clearance. In contrast, the nontargeted [89Zr]PEG-(DFB)4 showed low EPR-mediated accumulation with poor tumor tissue penetration. Overall, ACUPA conjugated targeted starPEGs significantly improve tumor retention with deep tumor tissue penetration in low EPR PC3-Pip xenografts. These data suggest that PSMA targeting with multivalent ACUPA ligands may be a generally applicable strategy to increase nanocarrier delivery to prostate cancer. These targeted multivalent nanocarriers with high tumor binding and low healthy tissue retention could be employed in imaging and therapeutic applications

Evaluation of 134Ce/134La as a PET Imaging Theranostic Pair for 225Ac α-Radiotherapeutics

225Ac-targeted α-radiotherapy is a promising approach to treating malignancies, including prostate cancer. However, α-emitting isotopes are difficult to image because of low administered activities and a low fraction of suitable γ-emissions. The in vivo generator 134Ce/134La has been proposed as a potential PET imaging surrogate for the therapeutic nuclides 225Ac and 227Th. In this report, we detail efficient radiolabeling methods using the 225Ac-chelators DOTA and MACROPA. These methods were applied to radiolabeling of prostate cancer imaging agents, including PSMA-617 and MACROPA-PEG4-YS5, for evaluation of their in vivo pharmacokinetic characteristics and comparison to the corresponding 225Ac analogs. Methods: Radiolabeling was performed by mixing DOTA/MACROPA chelates with 134Ce/134La in NH4OAc, pH 8.0, at room temperature, and radiochemical yields were monitored by radio-thin-layer chromatography. In vivo biodistributions of 134Ce-DOTA/MACROPA.NH2 complexes were assayed through dynamic small-animal PET/CT imaging and ex vivo biodistribution studies over 1 h in healthy C57BL/6 mice, compared with free 134CeCl3 In vivo, preclinical imaging of 134Ce-PSMA-617 and 134Ce-MACROPA-PEG4-YS5 was performed on 22Rv1 tumor-bearing male nu/nu-mice. Ex vivo biodistribution was performed for 134Ce/225Ac-MACROPA-PEG4-YS5 conjugates. Results: 134Ce-MACROPA.NH2 demonstrated near-quantitative labeling with 1:1 ligand-to-metal ratios at room temperature, whereas a 10:1 ligand-to-metal ratio and elevated temperatures were required for DOTA. Rapid urinary excretion and low liver and bone uptake were seen for 134Ce/225Ac-DOTA/MACROPA. NH2 conjugates in comparison to free 134CeCl3 confirmed high in vivo stability. An interesting observation during the radiolabeling of tumor-targeting vectors PSMA-617 and MACROPA-PEG4-YS5-that the daughter 134La was expelled from the chelate after the decay of parent 134Ce-was confirmed through radio-thin-layer chromatography and reverse-phase high-performance liquid chromatography. Both conjugates, 134Ce-PSMA-617 and 134Ce-MACROPA-PEG4-YS5, displayed tumor uptake in 22Rv1 tumor-bearing mice. The ex vivo biodistribution of 134Ce-MACROPA.NH2, 134Ce-DOTA and 134Ce-MACROPA-PEG4-YS5 corroborated well with the respective 225Ac-conjugates. Conclusion: These results demonstrate the PET imaging potential for 134Ce/134La-labeled small-molecule and antibody agents. The similar 225Ac and 134Ce/134La-chemical and pharmacokinetic characteristics suggest that the 134Ce/134La pair may act as a PET imaging surrogate for 225Ac-based radioligand therapies