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International Journal of Nanomedicine 2024This review article discusses the potential of nanomaterials in targeted therapy and immunomodulation for stroke-induced immunosuppression. Although nanomaterials have... (Review)
Review
This review article discusses the potential of nanomaterials in targeted therapy and immunomodulation for stroke-induced immunosuppression. Although nanomaterials have been extensively studied in various biomedical applications, their specific use in studying and addressing immunosuppression after stroke remains limited. Stroke-induced neuroinflammation is characterized by T-cell-mediated immunodepression, which leads to increased morbidity and mortality. Key observations related to immunodepression after stroke, including lymphopenia, T-cell dysfunction, regulatory T-cell imbalance, and cytokine dysregulation, are discussed. Nanomaterials, such as liposomes, micelles, polymeric nanoparticles, and dendrimers, offer advantages in the precise delivery of drugs to T cells, enabling enhanced targeting and controlled release of immunomodulatory agents. These nanomaterials have the potential to modulate T-cell function, promote neuroregeneration, and restore immune responses, providing new avenues for stroke treatment. However, challenges related to biocompatibility, stability, scalability, and clinical translation need to be addressed. Future research efforts should focus on comprehensive studies to validate the efficacy and safety of nanomaterial-based interventions targeting T cells in stroke-induced immunosuppression. Collaborative interdisciplinary approaches are necessary to advance the field and translate these innovative strategies into clinical practice, ultimately improving stroke outcomes and patient care.
Topics: Humans; Stroke; T-Lymphocytes; Nanostructures; Animals; Nanoparticles; Immunosuppression Therapy; Nanomedicine; Cytokines
PubMed: 38882535
DOI: 10.2147/IJN.S456632 -
Chemical Science Jun 2024The light-intensity dependence of multi-photon absorption (MPA) affords outstanding spatial control. Furthermore, compared to the higher-energy photons needed for...
The light-intensity dependence of multi-photon absorption (MPA) affords outstanding spatial control. Furthermore, compared to the higher-energy photons needed for analogous linear absorption, the lower-energy photons involved in MPA often correspond to important wavelengths, such as those of the biological and telecommunications "windows". It is therefore of crucial importance to develop molecules that exhibit outstanding MPA cross-sections. However, although progress has been made with two-photon absorption, there is currently a dearth of efficient instantaneous -photon absorbers ( > 2), a key reason being the scarcity of structure-property studies required to understand higher-order MPA. We herein report systematically-varied metallodendrimers up to third-generation in size, together with their nonlinear absorptive responses over the spectral range 600-2520 nm. We show that the dendrimers exhibit exceptional instantaneous three- to six-photon absorption cross-sections, with maximal values increasing with dendrimer generation and installation of solubilizing group, and we report that changing the groups at the dendrimer periphery can shift the wavelengths of the PA maxima. We also describe time-dependent DFT studies that have facilitated assignment of the key linear and nonlinear transitions and disclosed the crucial role of the metal in the outstanding MPA performance.
PubMed: 38873073
DOI: 10.1039/d4sc01127a -
Vaccine: X Aug 2024Scorpion envenoming (SE) is a public health problem in developing countries. In Algeria, the population exposed to the risk of SE was estimated at 86.45% in 2019. Thus,...
Scorpion envenoming (SE) is a public health problem in developing countries. In Algeria, the population exposed to the risk of SE was estimated at 86.45% in 2019. Thus, the development of a vaccine to protect the exposed population against scorpion toxins would be a major advance in the fight against this disease. This work aimed to evaluate the immunoprotective effect of a Multiple Antigenic Peptide against the Aah II toxin of scorpion, the most dangerous scorpion species in Algeria. The immunogen MAP1Aah2 was designed and tested accordingly. This molecule contains a B epitope, derived from Aah II toxin, linked by a spacer to a universal T epitope, derived from the tetanus toxin. The results showed that MAP1Aah2 was non-toxic despite the fact that its sequence was derived from Aah II toxin. The immunoenzymatic assay revealed that the 3 immunization regimens tested generated specific anti-MAP1Aah2 antibodies and cross-reacted with the toxin. Mice immunized with this immunogen were partially protected against mortality caused by challenge doses of 2 and 3 LD of the toxin. The survival rate and developed symptoms varied depending on the adjuvant and the challenge dose used. In the neutralization test, the immune sera of mice having received the immunogen with incomplete Freund's adjuvant neutralized a challenge dose of 2 LD50. Hence, the concept of using peptide dendrimers, based on linear epitopes of scorpion toxins, as immunogens against the parent toxin was established. However, the protective properties of the tested immunogen require further optimizations.
PubMed: 38868522
DOI: 10.1016/j.jvacx.2024.100503 -
Theranostics 2024The availability of non-invasive drug delivery systems capable of efficiently transporting bioactive molecules across the blood-brain barrier to specific cells at the...
The availability of non-invasive drug delivery systems capable of efficiently transporting bioactive molecules across the blood-brain barrier to specific cells at the injury site in the brain is currently limited. Delivering drugs to neurons presents an even more formidable challenge due to their lower numbers and less phagocytic nature compared to other brain cells. Additionally, the diverse types of neurons, each performing specific functions, necessitate precise targeting of those implicated in the disease. Moreover, the complex synthetic design of drug delivery systems often hinders their clinical translation. The production of nanomaterials at an industrial scale with high reproducibility and purity is particularly challenging. However, overcoming this challenge is possible by designing nanomaterials through a straightforward, facile, and easily reproducible synthetic process. In this study, we have developed a third-generation 2-deoxy-glucose functionalized mixed layer dendrimer () utilizing biocompatible and cost-effective materials a highly facile convergent approach, employing copper-catalyzed click chemistry. We further evaluated the systemic neuronal targeting and biodistribution of , and brain delivery of a neuroprotective agent pioglitazone () in a pediatric traumatic brain injury (TBI) model. The exhibits favorable characteristics including high water solubility, biocompatibility, biological stability, nanoscale size, and a substantial number of end groups suitable for drug conjugation. Upon systemic administration in a pediatric mouse model of traumatic brain injury (TBI), the localizes in neurons at the injured brain site, clears rapidly from off-target locations, effectively delivers , ameliorates neuroinflammation, and improves behavioral outcomes. The promising results coupled with a convenient synthetic approach for the construction of makes it a potential nanoplatform for addressing brain diseases.
Topics: Animals; Dendrimers; Neurons; Drug Delivery Systems; Deoxyglucose; Neuroprotective Agents; Mice; Pioglitazone; Blood-Brain Barrier; Brain Injuries, Traumatic; Brain; Brain Diseases; Humans; Disease Models, Animal; Tissue Distribution; Male
PubMed: 38855177
DOI: 10.7150/thno.95476 -
International Journal of Nanomedicine 2024Prostate cancer (PC) is the second most common cancer and the fifth most frequent cause of cancer death among men. Prostate-specific membrane antigen (PSMA) expression...
INTRODUCTION
Prostate cancer (PC) is the second most common cancer and the fifth most frequent cause of cancer death among men. Prostate-specific membrane antigen (PSMA) expression is associated with aggressive PC, with expression in over 90% of patients with metastatic disease. Those characteristics have led to its use for PC diagnosis and therapies with radiopharmaceuticals, antibody-drug conjugates, and nanoparticles. Despite these advancements, none of the current therapeutics are curative and show some degree of toxicity. Here we present the synthesis and preclinical evaluation of a multimodal, PSMA-targeted dendrimer-drug conjugate (PT-DDC), synthesized using poly(amidoamine) (PAMAM) dendrimers. PT-DDC was designed to enable imaging of drug delivery, providing valuable insights to understand and enhance therapeutic response.
METHODS
The PT-DDC was synthesized through consecutive conjugation of generation-4 PAMAM dendrimers with maytansinoid-1 (DM1) a highly potent antimitotic agent, Cy5 infrared dye for optical imaging, 2,2',2"-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA) chelator for radiolabeling with copper-64 and positron emission tomography tomography/computed tomography (PET/CT), lysine-urea-glutamate (KEU) PSMA-targeting moiety and the remaining terminal primary amines were capped with butane-1,2-diol. Non-targeted control dendrimer-drug conjugate (Ctrl-DDC) was formulated without conjugation of KEU. PT-DDC and Ctrl-DDC were characterized using high-performance liquid chromatography, matrix assisted laser desorption ionization mass spectrometry and dynamic light scattering. In vitro and in vivo evaluation of PT-DDC and Ctrl-DDC were carried out in isogenic human prostate cancer PSMA PC3 PIP and PSMA PC3 flu cell lines, and in mice bearing the corresponding xenografts.
RESULTS
PT-DDC was stable in 1×PBS and human blood plasma and required glutathione for DM1 release. Optical, PET/CT and biodistribution studies confirmed the in vivo PSMA-specificity of PT-DDC. PT-DDC demonstrated dose-dependent accumulation and cytotoxicity in PSMA PC3 PIP cells, and also showed growth inhibition of the corresponding tumors. PT-DDC did not accumulate in PSMA PC3 flu tumors and did not inhibit their growth. Ctrl-DDC did not show PSMA specificity.
CONCLUSION
In this study, we synthesized a multimodal theranostic agent capable of delivering DM1 and a radionuclide to PSMA tumors. This approach holds promise for enhancing image-guided treatment of aggressive, metastatic subtypes of prostate cancer.
Topics: Dendrimers; Male; Humans; Glutamate Carboxypeptidase II; Prostatic Neoplasms; Antigens, Surface; Cell Line, Tumor; Animals; Mice; Positron Emission Tomography Computed Tomography; Drug Delivery Systems
PubMed: 38832336
DOI: 10.2147/IJN.S454128 -
Analytical Chemistry Jun 2024Ion mobility mass spectrometry (IM-MS) measures the mass, size, and shape of ions in the same experiment, and structural information is provided via collision...
Ion mobility mass spectrometry (IM-MS) measures the mass, size, and shape of ions in the same experiment, and structural information is provided via collision cross-section (CCS) values. The majority of commercially available IM-MS instrumentation relies on the use of CCS calibrants, and here, we present data from a family of poly(l-lysine) dendrimers and explore their suitability for this purpose. In order to test these compounds, we employed three different IM-MS platforms (Agilent 6560 IM-QToF, Waters Synapt G2, and a home-built variable temperature drift tube IM-MS) and used them to investigate six different generations of dendrimers in two buffer gases (helium and nitrogen). Each molecule gives a highly discrete CCS distribution suggestive of single conformers for each / value. The CCS values of this series of molecules (molecular weight: 330-16,214 Da) range from 182 to 2941 Å, which spans the CCS range that would be found by many synthetic molecules including supramolecular compounds and many biopolymers. The CCS values for each charge state were highly reproducible in day-to-day analysis on each instrument, although we found small variations in the absolute CCS values between instruments. The rigidity of each dendrimer was probed using collisionally activated and high-temperature IM-MS experiments, where no evidence for a significant CCS change ensued. Taken together, this data indicates that these polymers are candidates for CCS calibration and could also help to reconcile differences found in CCS measurements on different instrument geometries.
Topics: Dendrimers; Polylysine; Ion Mobility Spectrometry; Mass Spectrometry; Molecular Conformation
PubMed: 38812282
DOI: 10.1021/acs.analchem.4c00099 -
Polymers May 2024Cardiovascular diseases (CVDs), the world's most prominent cause of mortality, continue to be challenging conditions for patients, physicians, and researchers alike.... (Review)
Review
Cardiovascular diseases (CVDs), the world's most prominent cause of mortality, continue to be challenging conditions for patients, physicians, and researchers alike. CVDs comprise a wide range of illnesses affecting the heart, blood vessels, and the blood that flows through and between them. Advances in nanomedicine, a discipline focused on improving patient outcomes through revolutionary treatments, imaging agents, and ex vivo diagnostics, have created enthusiasm for overcoming limitations in CVDs' therapeutic and diagnostic landscapes. Nanomedicine can be involved in clinical purposes for CVD through the augmentation of cardiac or heart-related biomaterials, which can be functionally, mechanically, immunologically, and electrically improved by incorporating nanomaterials; vasculature applications, which involve systemically injected nanotherapeutics and imaging nanodiagnostics, nano-enabled biomaterials, or tissue-nanoengineered solutions; and enhancement of sensitivity and/or specificity of ex vivo diagnostic devices for patient samples. Therefore, this review discusses the latest studies based on applying organic nanoparticles in cardiovascular illness, including drug-conjugated polymers, lipid nanoparticles, and micelles. Following the revised information, it can be concluded that organic nanoparticles may be the most appropriate type of treatment for cardiovascular diseases due to their biocompatibility and capacity to integrate various drugs.
PubMed: 38794614
DOI: 10.3390/polym16101421 -
Pharmaceutics May 2024Worldwide cancer statistics have indicated about 20 million new cancer cases and over 10 million deaths in 2022 (according to data from the International Agency for... (Review)
Review
Worldwide cancer statistics have indicated about 20 million new cancer cases and over 10 million deaths in 2022 (according to data from the International Agency for Research on Cancer). One of the leading cancer treatment strategies is chemotherapy, using innovative drug delivery systems (DDSs). Self-immolative domino dendrimers (SIDendr) for triggered anti-cancer drugs appear to be a promising type of DDSs. The present review provides an up-to-date survey on the contemporary advancements in the field of SIDendr-based anti-cancer drug delivery systems (SIDendr-ac-DDSs) through an exhaustive analysis of the discovery and application of these materials in improving the pharmacological effectiveness of both novel and old drugs. In addition, this article discusses the designing, chemical structure, and targeting techniques, as well as the properties, of several SIDendr-based DDSs. Approaches for this type of targeted DDSs for anti-cancer drug release under a range of stimuli are also explored.
PubMed: 38794329
DOI: 10.3390/pharmaceutics16050668 -
Biological Response Following the Systemic Injection of PEG-PAMAM-Rhodamine Conjugates in Zebrafish.Pharmaceutics Apr 2024Numerous therapeutic and diagnostic approaches used within a clinical setting depend on the administration of compounds via systemic delivery. Biomaterials at the...
Numerous therapeutic and diagnostic approaches used within a clinical setting depend on the administration of compounds via systemic delivery. Biomaterials at the nanometer scale, as dendrimers, act as delivery systems by improving cargo bioavailability, circulation time, and the targeting of specific tissues. Although evaluating the efficacy of pharmacological agents based on nanobiomaterials is crucial, conducting toxicological assessments of biomaterials is essential for advancing clinical translation. Here, a zebrafish larvae model was explored to assess the biocompatibility of poly(amido amine) (PAMAM), one of the most exploited dendrimers for drug delivery. We report the impact of a systemic injection of polyethylene glycol (PEG)-modified G4 PAMAM conjugated with rhodamine (Rho) as a mimetic drug (PEG-PAMAM-Rho) on survival, animal development, inflammation, and neurotoxicity. A concentration- and time-dependent effect was observed on mortality, developmental morphology, and innate immune system activation (macrophages). Significant effects in toxicological indicators were reported in the highest tested concentration (50 mg/mL PEG-PAMAM-Rho) as early as 48 h post-injection. Additionally, a lower concentration of PEG-PAMAM-Rho (5 mg/mL) was found to be safe and subsequently tested for neurotoxicity through behavioral assays. In accordance, no significative signs of toxicity were detected. In conclusion, the dose response of the animal was assessed, and the safe dosage for future use in theragnostics was defined. Additionally, new methodologies were established that can be adapted to further studies in toxicology using other nanosystems for systemic delivery.
PubMed: 38794270
DOI: 10.3390/pharmaceutics16050608 -
Microorganisms May 2024Conjugation of carbohydrates to nanomaterials has been extensively studied and recognized as an alternative in the biomedical field. Dendrimers synthesized with mannose...
Conjugation of carbohydrates to nanomaterials has been extensively studied and recognized as an alternative in the biomedical field. Dendrimers synthesized with mannose at the end group and with entrapped zero-valent copper/silver could be a potential candidate against bacterial proliferation. This study is aimed at investigating the bactericidal activity of metal-glycodendrimers. The Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction was used to synthesize a new mannosylated dendrimer containing 12 mannopyranoside residues in the periphery. The enterotoxigenic fimbriae 4 (ETEC:F4) viability, measured at 600 nm, showed the half-inhibitory concentration (IC) of metal-free glycodendrimers (D), copper-loaded glycodendrimers (D:Cu) and silver-loaded glycodendrimers (D:Ag) closed to 4.5 × 10, 3.5 × 10 and to 1.0 × 10 µg/mL, respectively, and minimum inhibitory concentration (MIC) of D, D:Cu and D:Ag of 2.0, 1.5 and 1.0 × 10 µg/mL, respectively. The release of bacteria contents onto broth and the inhibition of ETEC:F4 biofilm formation increased with the number of metallo-glycodendrimer materials, with a special interest in silver-containing nanomaterial, which had the highest activity, suggesting that glycodendrimer-based materials interfered with bacteria-bacteria or bacteria-polystyrene interactions, with bacteria metabolism and can disrupt bacteria cell walls. Our findings identify metal-mannose-dendrimers as potent bactericidal agents and emphasize the effect of entrapped zero-valent metal against ETEC:F4.
PubMed: 38792795
DOI: 10.3390/microorganisms12050966