Search Results (1,061)

Phthalocyanines (Pcs) are well-established photosensitizers in photodynamic therapy, valued for their strong light absorption, high singlet oxygen generation, and photostability. Recent advances have focused on covalently conjugating Pcs, particularly zinc phthalocyanines (ZnPcs), with a wide range of small bioactive molecules to improve selectivity, efficacy, and multifunctionality. These conjugates combine light-activated reactive oxygen species (ROS) production with targeted delivery and controlled release, offering enhanced treatment precision and reduced off-target toxicity. Chemotherapeutic agent conjugates, including those with erlotinib, doxorubicin, tamoxifen, and camptothecin, demonstrate receptor-mediated uptake, pH-responsive release, and synergistic anticancer effects, even overcoming multidrug resistance. Beyond oncology, ZnPc conjugates with antibiotics, anti-inflammatory drugs, antiparasitics, and antidepressants extend photodynamic therapy’s scope to antimicrobial and site-specific therapies. Targeting moieties such as folic acid, biotin, arginylglycylaspartic acid (RGD) and epidermal growth factor (EGF) peptides, carbohydrates, and amino acids have been employed to exploit overexpressed receptors in tumors, enhancing cellular uptake and tumor accumulation. Fluorescent dye and porphyrinoid conjugates further enrich these systems by enabling imaging-guided therapy, efficient energy transfer, and dual-mode activation through pH or enzyme-sensitive linkers. Despite these promising strategies, key challenges remain, including aggregation-induced quenching, poor aqueous solubility, synthetic complexity, and interference with ROS generation. In this review, the examples of Pc-based conjugates were described with particular interest on the synthetic procedures and optical properties of targeted compounds. Full article

Palindromic antimicrobial peptides (PAMs) constitute versatile scaffolds for the design and optimization of anticancer agents with applications in therapy, diagnosis, and/or monitoring. In the present study, fluorolabeled peptides derived from the palindromic sequence RWQWRWQWR containing fluorescent probes, such as 2-Aminobenzoyl, 5(6)-Carboxyfluorescein, and Rhodamine B, were obtained. RP-HPLC analysis revealed that the palindromic peptide conjugated to Rhodamine B (RhB-RWQWRWQWR) exhibited the presence of isomers, likely corresponding to the open-ring and spiro-lactam forms of the fluorescent probe. This equilibrium is dependent on the peptide sequence, as the RP-HPLC analysis of dimeric peptide (RhB-RRWQWR-hF-KKLG)₂K-Ahx did not reveal the presence of isomers. The antibacterial activity of the fluorescent peptides depends on the probe attached to the sequence and the bacterial strain tested. Notably, some fluorescent peptides showed activity against reference strains as well as sensitive, resistant, and multidrug-resistant clinical isolates of E. coli, S. aureus, and E. faecalis. Fluorolabeled peptides 1-Abz (MIC = 62 µM), RhB-1 (MIC = 62 µM), and Abz-1 (MIC = 31 µM) exhibited significant activity against clinical isolates of E. coli, S. aureus, and E. faecalis, respectively. The RhB-1 (IC₅₀ = 61 µM), Abz-1 (IC₅₀ = 87 µM), and RhB-2 (IC₅₀ = 35 µM) peptides exhibited a rapid, significant, and concentration-dependent cytotoxic effect on HeLa cells, accompanied by morphological changes characteristic of apoptosis. RhB-1 (IC₅₀ = 18 µM) peptide also exhibited significant cytotoxic activity against breast cancer cells MCF-7. These conjugates remain valuable for elucidating the possible mechanisms of action of these novel anticancer peptides. Rhodamine-labeled peptides displayed cytotoxicity comparable to that of their unlabeled analogues, suggesting that cellular internalization constitutes a critical early step in their mechanism of action. These findings suggest that cell death induced by both unlabeled and fluorolabeled peptides proceeds predominantly via apoptosis and is likely contingent upon peptide internalization. Functionalization at the N-terminal end of the palindromic sequence can be evaluated to develop systems for transporting non-protein molecules into cancer cells. Full article

Background/Objectives: Intramuscular immunization elicits systemic IgG and is the primary route of vaccine administration in humans. However, there is growing interest in utilizing other routes of administration to tailor antibody profiles, increase immunity at primary sites of infection, simplify administration, and eliminate needle waste. Here, we investigated the antibody profiles elicited by immunization with bacteriophage virus-like particle vaccine platforms at various routes of administration. Methods: We chose two model bacteriophage vaccines for investigation: bacteriophage MS2 virus-like particles (VLPs) recombinantly displaying a short, conserved peptide from Chlamydia trachomatis major outer membrane protein (MS2) and bacteriophage Qβ VLPs displaying oxycodone through chemical conjugation (Qβ). We comprehensively characterized the antibodies elicited systemically and at various mucosal sites when the vaccines were administered intramuscularly, intranasally or periocularly with or without an intramuscular prime using various prime/boost schemes. Results: Intranasal and periocular immunization elicited robust mucosal and systemic IgA responses for both MS2 and Qβ. The intramuscular prime followed by intranasal or periocular boosts elicited broad antibody responses, and increased antibodies titers at certain anatomical sites. Conclusions: These findings demonstrate the tractability of bacteriophage VLP-based vaccines in generating specific antibody profiles based on the prime–boost regimen and route of administration. Full article

Gastric cancer (GC) remains a major cause of cancer-related mortality worldwide, with human epidermal growth factor receptor 2 (HER2)-positive disease representing a clinically relevant subset. Trastuzumab combined with chemotherapy is the standard first-line treatment in advanced settings, following the landmark ToGA trial. However, resistance to trastuzumab has emerged as a significant limitation, prompting the need for more effective second-line therapies. Trastuzumab deruxtecan, a novel antibody–drug conjugate (ADC) composed of trastuzumab linked to a cytotoxic payload, has demonstrated promising efficacy in trastuzumab-refractory, HER2-positive GC, including cases with heterogeneous HER2 expression. Other HER2-targeted ADCs are also under investigation as potential alternatives. In addition, strategies to overcome resistance include HER2-specific immune-based therapies, such as peptide vaccines and chimeric antigen receptor T cell therapies, as well as antibodies targeting distinct HER2 domains or downstream signaling pathways like PI3K/AKT. These emerging approaches aim to improve efficacy in both HER2-high and HER2-low GC. As HER2-targeted treatments evolve, addressing resistance mechanisms and optimizing therapy for broader patient populations is critical. This review discusses current and emerging HER2-directed strategies in GC, focusing on trastuzumab deruxtecan and beyond, and outlines future directions to improve outcomes for patients with HER2-positive GC across all clinical settings. Full article

Background/Objectives: A nanostructured membrane of polycaprolactone (a synthetic polymer) was synthesized using an electrospinning technique aiming to enhance its hydrophilicity and rate of degradation by surface modification via aminolysis. Since polycaprolactone nanofibrous films are naturally hydrophobic and with slow degradation, which restricts their use in biological systems, amino groups were added to the fiber surface using the aminolysis technique, greatly increasing the wettability of the membranes. Methods: Polycaprolactone nanofibrous membranes were synthesized via the electrospinning technique and surface modification by aminolysis. Trypsin, pepsin, and pancreatin were conjugated onto the aminolyzed PNF surface to further strengthen biocompatibility by enhancing the hydrophilicity, porosity, and biodegradation rate. SEM, FTIR, EDX, and liquid displacement method were performed to investigate proteolytic efficiency and morphological and physical characteristics such as hydrophilicity, porosity, and degradation rates. Results: Enzyme activity tests, which showed a zone of clearance, validated the successful enzyme conjugation and stability over a wide range of pH and temperatures. Scanning electron microscopy (SEM) confirms the smooth morphology of nanofibers with diameters ranging from 150 to 950 nm. Fourier transform infrared spectroscopy (FTIR) revealed the presence of O–H, C–O, C=O, C–N, C–H, and O–H functional groups. Energy-dispersive X-ray (EDX) elemental analysis indicates the presence of carbon, oxygen, and nitrogen atoms owing to the presence of peptide and amide bonds. The liquid displacement technique and contact angle proved that Pepsin-PNFs possess notably increased porosity (88.50% ± 0.31%) and hydrophilicity (57.6° ± 2.3 (L), 57.9° ± 2.5 (R)), respectively. Pancreatin-PNFs demonstrated enhanced enzyme activity and degradation rate on day 28 (34.61%). Conclusions: These enzyme-conjugated PNFs thus show improvements in physicochemical properties, making them ideal candidates for various biomedical applications. Future studies must aim for optimization of enzyme conjugation and in vitro and in vivo performance to investigate the versatility of these scaffolds. Full article

A significant issue in healthcare is the growing prevalence of antibiotic-resistant strains. Therefore, it is necessary to develop strategies for discovering new antibacterial compounds, either by identifying natural products or by designing semisynthetic or synthetic compounds with this property. In this context, a great deal of research has recently been carried out on antimicrobial peptides (AMPs), which are natural, amphipathic, low-molecular-weight molecules that act by altering the cell surface and/or interfering with cellular activities essential for life. Progress is also being made in developing strategies to enhance the activity of these compounds through their association with other molecules. In addition to identifying AMPs, it is essential to ensure that they maintain their integrity after passing through the digestive tract and exhibit adequate activity against their targets. Significant advances are being made in relation to analyzing various types of conjugates and carrier systems, such as nanoparticles, vesicles, hydrogels, and carbon nanotubes, among others. In this work, we review the current knowledge of different types of AMPs, their mechanisms of action, and strategies to improve performance. Full article

Background/Objective: Programmed cell death ligand-1 (PD-L1), which is overexpressed in certain tumors, inhibits the body’s natural immune response by providing an “off” signal that enables cancer cells to evade the immune system. It has been demonstrated that [¹⁷⁷Lu]Lu-DOTA-iPD-L1 (PD-L1 inhibitor cyclic peptide) promotes immune responses. This study aimed to synthesize and evaluate [¹⁸F]AlF-NOTA-iPD-L1 as a novel radiotracer for PD-L1 positron emission tomography (PET) imaging and as a potential theranostic pair for [¹⁷⁷Lu]Lu-DOTA-iPD-L1. Methods: The NOTA-iPD-L1 peptide conjugate was synthesized and characterized by U.V.-vis, I.R.-FT, and UPLC-mass spectroscopies. Radiolabeling was performed using [¹⁸F]AlF as the precursor, and the radiochemical purity (HPLC), partition coefficient, and serum stability were assessed. Cellular uptake and internalization (in 4T1 triple-negative breast cancer cells), binding competition, immunofluorescence, and Western blot assays were applied for the radiotracer in vitro characterization. Biodistribution in mice bearing 4T1 tumors was performed, and molecular imaging (Cerenkov images) of [¹⁸F]AlF-NOTA-iPD-L1 and [¹⁷⁷Lu]Lu-DOTA-iPD-L1 in the same mouse was obtained. Results: [¹⁸F]AlF-NOTA-iPD-L1 was prepared with a radiochemical purity greater than 97%, and it demonstrated high in vitro and in vivo stability, as well as specific recognition by the PD-L1 protein (IC₅₀ = 9.27 ± 2.69 nM). Biodistribution studies indicated a tumor uptake of 6.4% ± 0.9% ID/g at 1-hour post-administration, and Cerenkov images showed a high tumor uptake of both [¹⁸F]AlF-NOTA-iPD-L1 and ¹⁷⁷Lu-iPD-L1 in the same mouse. Conclusions: These results warrant further studies to evaluate the clinical usefulness of [¹⁸F]AlF-NOTA-iPD-L1/[¹⁷⁷Lu]Lu-DOTA-iPD-L1 as a radiotheranostic pair in combination with anti-PD-L1/PD1 immunotherapy. Full article

Antimicrobial peptides (AMPs) represent a powerful support to conventional antibiotics in addressing the global challenge of antimicrobial resistance (AMR). Their broad-spectrum antimicrobial activity and unique mechanisms of action enable diverse potential applications, including combating multidrug-resistant pathogens, immune modulation, and cancer therapy. Their clinical implementation is hindered by challenges such as toxicity, instability, and high production costs. Recent advances in AMP design, optimization, and delivery mechanisms such as nanoparticle conjugation and rational engineering have enhanced their efficacy, stability, and specificity. Integrating AMPs into precision medicine and combining them with existing therapies promises to overcome current limitations. With ongoing advancements, AMPs have the potential to redefine infection management and possibly other medical problems. Full article

Background/Objectives: PEGylated liposomes are widely recognized for their biocompatibility and capacity to extend systemic circulation via “stealth” properties. However, the PEG corona often limits tumor penetration and cellular internalization. Targeting matrix metalloproteinase-2 (MMP-2), frequently upregulated in breast cancer stroma, presents an opportunity to enhance tissue-specific drug delivery. In this study, we engineered MMP-2-responsive GPLGVRG peptide-modified cleavable PEGylated liposomes for targeted paclitaxel (PTX) delivery. Methods: Molecular docking simulations employed the MMP-2 crystal structure (PDB ID: 7XJO) to assess GPLGVRG peptide binding affinity. A cleavable, enzyme-sensitive peptide-PEG conjugate (Chol-PEG_2K-GPLGVRG-PEG_5K) was synthesized via small-molecule liquid-phase synthesis and characterized by ¹H NMR and MALDI-TOF MS. Liposomes incorporating this conjugate (S-Peps-PEG_5K) were formulated to evaluate whether MMP-2-mediated peptide degradation triggers detachment of long-chain PEG moieties, thereby enhancing internalization by 4T1 breast cancer cells. Additionally, the effects of tumor microenvironmental pH (~6.5) and MMP-2 concentration on drug release dynamics were investigated. Results: Molecular docking revealed robust GPLGVRG-MMP-2 interactions, yielding a binding energy of −7.1 kcal/mol. The peptide formed hydrogen bonds with MMP-2 residues Tyr A:23 and Arg A:53 (bond lengths: 2.4–2.5 Å) and engaged in hydrophobic contacts, confirming MMP-2 as the primary recognition site. Formulations containing 5 mol% Chol-PEG_2K-GPLGVRG-PEG_5K combined with 0.15 µg/mL MMP-2 (S-Peps-PEG_5K +MMP) exhibited superior internalization efficiency and significantly reduced clonogenic survival compared to controls. Notably, acidic pH (~6.5) induced MMP-2-mediated cleavage of the GPLGVRG peptide, accelerating S-Peps-PEG_5K dissociation and facilitating drug release. Conclusions: MMP-2-responsive, cleavable PEGylated liposomes markedly improve PTX accumulation and controlled release at tumor sites by dynamically modulating their stealth properties, offering a promising strategy to enhance chemotherapy efficacy in breast cancer. Full article

This work aimed to evaluate two albumin affinity structure-containing peptide-radionuclide conjugate drugs, INER-PP-F11N-1 and INER-PP-F11N-2, for the diagnosis/treatment of cholecystokinin receptor subtype 2 (CCK2R)-overexpressing cancers. We developed In-111- and Lu-177-labeled INER-PP-F11N radiopharmaceuticals and compared them with the current PP-F11N to investigate metabolic stability, biodistribution, SPECT/CT imaging, and therapeutic responses in CCK2R-expressing tumor xenograft mice. The metabolic stability of [¹¹¹In]In/[¹⁷⁷Lu]Lu-INER-PP-F11N remained above 90% for up to 144 h after labeling, indicating that the compound is highly stable under in vitro conditions. INER-PP-F11N showed 27% and 11% higher cellular uptake and internalization than PP-F11N, respectively. In vivo SPECT/CT imaging confirmed that INER-PP-F11N could accumulate at the tumor site of mice 24 h after receiving the two radiopharmaceutical agents. Biodistribution analysis revealed a significantly greater tumor uptake and reduced accumulation of INER-PP-F11N in the kidneys compared with PP-F11N. Furthermore, INER-PP-F11N significantly inhibited the growth of the CCK2R-overexpressing tumors in mice. The INER-PP-F11N radiopharmaceutical was superior as a theragnostic agent compared with the current PP-F11N. Our study suggests that INER-PP-F11N may be an innovative radiopharmaceutical agent for CCK2R-overexpressing tumors. Full article

Background: Metastatic prostate cancer (mPrC), with a median survival of under 2 years, represents an important unmet medical need which may benefit from the development of more effective targeted drug delivery systems. Several cell surface receptors have been identified as candidates for targeted drug delivery to mPrC cells; however, these receptors were selected for their overabundance on PrC cells rather than for their suitability for targeted delivery and uptake of cytotoxic drug payloads. Methods: We describe a novel, unbiased strategy to isolate peptides that fulfill functional criteria required for effective intracellular drug delivery and the specific cytotoxicity of PrC cells without prior knowledge of the targeted receptor. Phage clones displaying 7-mer cyclic peptides were negatively selected in vivo and then positively biopanned through a series of parent and drug-resistant mPrC cells. Peptides from the internalized clones were then subjected to a panel of biochemical and functional tests that led to the selection of several peptide candidates. Results: The selected peptides do not bind PSMA. Peptide-drug conjugates (PDCs) incorporating one of the peptides selectively killed wild-type and drug-resistant PrC cell lines and patient PrC cells but not normal prostate tissue cells in vitro. The PDC also halted the growth of PC3 tumors in a xenograft model. Conclusions: Our study demonstrates that adding unbiased, functional criteria into drug carrier selection protocols can lead to the discovery of novel peptides with appropriate properties required for effective targeted drug delivery into target cancer cells. Full article

Background: Cell-penetrating peptides cross cell membrane barriers while carrying cargoes in a functional form. Our work identified two novel lung-targeting peptides, S7A and R11A. Here, we present studies on biodistribution, the cell types targeted, and an in vitro proof of application. Methods: Studies were performed in human bronchial epithelial cells (HBECs) with and without various endocytic inhibitors, and coincubation with fluorescently labeled transferrin or endocytic markers. Cyclic R11A (cR11A) was conjugated to siRNA duplexes and anti-viral activity against SARS-CoV-2 was tested. Biodistribution studies were performed by injecting wild-type mice with fluorescently labeled peptides, and various circulation times were allowed for, as well as cross-staining of lung sections or isolated single cells with various cellular markers, followed by fluorescence-activated cell sorting or confocal microscopy. Results: cR11A showed peak uptake in 15 min, with the highest uptake in airway epithelial type II (ATII) cells, followed by p63+ basal cells and ionocytes. Cyclization increased transduction efficiencies ~100-fold. Endocytosis studies showed a decrease in peptide uptake by pre-treatment with Pitstop2 but not Amiloride or Nystatin. Endocytic marker Lamp1 showed colocalization at the earliest time point, with the escape of the peptide from endocytic vesicles later. cR11A conjugated to ant-spike and anti-envelop proteins showed anti-viral effects with an EC₉₀ of 0.6 μM and 1.0 µM, respectively. Conclusions: We have identified a novel peptide, cR11A, that targets ATII, basal cells, and ionocytes, the cyclization of which increased transduction efficiency in vitro and in vivo. The uptake mechanism appears to be via clathrin-mediated endocytosis with escape from endocytic vesicles. cR11A can act as a vector to deliver anti-viral siRNA to epithelial cells. Full article

Background/Objectives: The increasing prevalence of multidrug-resistant bacteria presents a major global health challenge, prompting a search for innovative antimicrobial strategies. This study aimed to develop and evaluate a novel nanobiostructure combining alumina nanoparticles (NPs) with the antimicrobial peptide lunatin-1 (Lun-1), forming peptide-functionalized nanofilaments. The main objective was to investigate how the site of peptide functionalization (C-terminal vs. N-terminal) affects membrane interactions and antibacterial activity. Methods: NP–peptide conjugates were synthesized via covalent bonding between lun-1 and alumina NP and characterized using transmission electron microscopy (TEM), X-ray diffraction (XRD), zeta potential analysis, dynamic light scattering (DLS), Fourier-transform infrared (FTIR), and solid-state ¹³C NMR. Antibacterial activities were assessed against different Gram-positive and Gram-negative strains. Biophysical analyses, including circular dichroism (CD), isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), and solid-state ²H NMR, were employed to evaluate peptide–membrane interactions in the presence of membrane-mimetic vesicles composed of POPC:POPG (3:1) and DMPC:DMPG (3:1). Results: Characterization confirmed the successful formation of NP–peptide nanofilaments. Functionalization at the N-terminal significantly influenced both antibacterial activity and peptide conformation compared to C-terminal attachment. Biophysical data demonstrated stronger membrane interaction and greater membrane disruption when lun-1 was conjugated at the N-terminal. Conclusions: The site of peptide conjugation plays a crucial role in modulating the biological and biophysical properties of NP–lunatin-1 conjugates. C-terminal attachment of lunatin-1 retains both membrane interaction and antibacterial efficacy, making it a promising strategy for the design of peptide-based nanotherapeutics targeting resistant pathogens. Full article

Global concerns about environmental pollution, poor waste management, and the rise in antimicrobial resistance due to uncontrolled antibiotic use have driven researchers to seek alternative, multifaceted solutions. Plants, animals, microorganisms, and their processing wastes serve as valuable sources of natural biopolymers and bioactive compounds. Through nanotechnology, these can be assembled into formulations with enhanced antimicrobial properties, high safety, and low toxicity. This review explores polysaccharides, including chitosan, alginate, starch, pectin, cellulose, hemicellulose, gums, carrageenan, dextran, pullulan, and hyaluronic acid, used in nanotechnology, highlighting their advantages and limitations as nanocarriers. Addressing the global urgency for alternative antimicrobials, we examined natural compounds derived from plants, microorganisms, and animals, such as phytochemicals, bacteriocins, animal antimicrobial peptides, and proteins. Focusing on their protection and retained activity, this review discusses polysaccharide-based nanoformulations with natural antimicrobials, including nanoparticles, nanoemulsions, nanocapsules, nanoplexes, and nanogels. Special emphasis is placed on strategies and formulations for the encapsulation, entrapment, and conjugation of natural compounds using polysaccharides as protective carriers and delivery systems, including a brief discussion on their future applications, prospects, and challenges in scaling up. Full article

Seliciclib, a cyclin-dependent kinase 5 (CDK5) inhibitor, has demonstrated neuroprotective potential. However, its therapeutic application is limited by poor permeability across the blood–brain barrier (BBB). In this study, polymeric nanoparticles (NPs) modified with a BBB-targeting peptide ligand (His-Ala-Ile-Tyr-Pro-Arg-His) were employed to encapsulate seliciclib. In vitro transport studies showed that the peptide-modified NPs exhibited significantly greater translocation across a bEnd.3 cell monolayer compared to unmodified NPs. Furthermore, in vivo biodistribution analysis revealed that the brain accumulation of peptide-modified NPs was 3.38-fold higher than that of unmodified NPs. Notably, the peptide-conjugated, seliciclib-loaded NPs demonstrated a significant neuroprotective effect against the neurotoxin 1-methyl-4-phenylpyridinium (MPP⁺) in differentiated SH-SY5Y cells. Full article