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In photodynamic therapy (PDT), the low absorptivity of photosensitizers in an aqueous environment reduces singlet oxygen generation efficiency and thereby decreases photosensitizing efficacy in biological conditions. To circumvent this problem, we designed a phthalocyanine-poly-L-glutamic acid conjugate ( 1-PG ) made from a new phthalocyanine ( Pc 1 ) monofunctionalized to allow adequate conjugation to PGA. The resulting 1-PG conjugate retained high absorptivity in the near-infrared (NIR) region at its λ max 675 nm in an aqueous environment. The 1-PG conjugate demonstrated good singlet oxygen generation efficiency, increased uptake by 4 T1 breast cancer cells via clathrin-mediated endocytosis, and enhanced photocytotoxic efficacy. The conjugate also displayed a high light–dark toxicity ratio, approximately 1.5-fold greater than zinc phthalocyanine at higher concentration (10 μM), an important feature for the reduction of dark toxicity and unwanted side effects. These results suggest that the 1-PG conjugate could be a useful alternative for deep tissue treatment with enhanced anti-cancer (PDT) efficacy. [ABSTRACT FROM AUTHOR]

Abstract: To enhance the stability of the anticancer drug gemcitabine (2′-deoxy-2′,2′-difluorocytidine), it was conjugated to poly-l-glutamic acid (PG-H) via a carbodiimide reaction. The synthesised poly-l-glutamic acid-gemcitabine (PG-G) was purified and characterised by using SDS-PAGE to estimate its molecular weight, HPLC to determine its purity and degree of drug loading, and NMR to elucidate the structure. In vitro aqueous hydrolytic studies showed that the gemcitabine release from the polymeric drug conjugate was pH dependent, and that the conjugation to PG-H improved its stability in human plasma. The release of the bound gemcitabine from PG-G in plasma was mediated by a hydrolytic process. It began with a lag phase, followed by linear release between 12 and 48h, and reached equilibrium at 72h with 51% of the gemcitabine released. In vitro cytotoxicity studies using MCF-7 and MDA-MB-231 human mammary cancer cells, as well as human dermal fibroblasts (HDF), showed that PG-G displayed a lower dose dependent cytotoxic effect with respect to the parent drug gemcitabine. On the other hand, in 4T1 mouse mammary tumour cells, PG-G and gemcitabine showed similar toxicities. Gemcitabine was more than likely released hydrolytically from PG-G and taken up by MCF-7, MDA-MB-231 and HDF, whereas both released gemcitabine and PG-G were taken up by 4T1 to mediate the observed cytotoxicities. The improved stability and extended sustained release profile may render PG-G a potential anticancer prodrug. [Copyright &y& Elsevier]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the cells through the binding of its spike protein (S-protein) to the cell surface-expressing angiotensin-converting enzyme 2 (ACE2). Thus, inhibition of S-protein-ACE2 binding may impede SARS-CoV-2 cell entry and attenuate the progression of Coronavirus disease 2019 (COVID-19). In this study, an electrochemical impedance spectroscopy-based biosensing platform consisting of a recombinant ACE2-coated palladium nano-thin-film electrode as the core sensing element was fabricated for the screening of potential inhibitors against S-protein-ACE2 binding. The platform could detect interference of small analytes against S-protein-ACE2 binding at low analyte concentration and small volume (0.1 μg/mL and ~1 μL, estimated total analyte consumption < 4 pg) within 21 min. Thus, a few potential inhibitors of S-protein-ACE2 binding were identified. This includes (2S,3aS,6aS)-1-((S)–N-((S)-1-Carboxy-3-phenylpropyl)alanyl)tetrahydrocyclopenta[b] pyrrole-2-carboxylic acid (ramiprilat) and (2S,3aS,7aS)-1-[(2S)-2-[[(2S)-1-Carboxybutyl]amino]propanoyl]-2,3,3a,4,5,6,7,7a-octahydroindole-2-carboxylic acid (perindoprilat) that reduced the binding affinity of S-protein to ACE2 by 72% and 67%; and SARS-CoV-2 in vitro infectivity to the ACE2-expressing human oral cavity squamous carcinoma cells (OEC-M1) by 36.4 and 20.1%, respectively, compared to the PBS control. These findings demonstrated the usefulness of the developed biosensing platform for the rapid screening of modulators for S-protein-ACE2 binding. • A sensitive sensing platform was developed to detect modulators that affect the SARS-CoV-2 and ACE2 interaction. • The modulators can be detected in a small volume of 1 μL with the total analyte consumption <4 pg. • The bio-probes can be conjugated to the flexible nano-Pd thin film electrode can be achieved within 15–20 min. • Potential leads, i.e., ramiprilat, and perindoprilat, that reduce the risks of the SARS-CoV-2 infection were identified. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) has recently emerged as a potential valuable alternative to treat microbial infections. In PDT, singlet oxygen is generated in the presence of photosensitisers and oxygen under light irradiation of a specific wavelength, causing cytotoxic damage to bacteria. This review highlights different generations of photosensitisers and the common characteristics of ideal photosensitisers. It also focuses on the emergence of ruthenium and more specifically on Ru(II) polypyridyl complexes as metal-based photosensitisers used in antimicrobial photodynamic therapy (aPDT). Their photochemical and photophysical properties as well as structures are discussed while relating them to their phototoxicity. The use of Ru(II) complexes with recent advancements such as nanoformulations, combinatory therapy and photothermal therapy to improve on previous shortcomings of the complexes are outlined. Future perspectives of these complexes used in two-photon PDT, photoacoustic imaging and sonotherapy are also discussed. This review covers the literature published from 2017 to 2023. The review discussed the use of Ru(II) polypyridyl complexes with structural modifications as antibacterial photodynamic therapy agents together with recent advancements such as nanoformulations, combinatory therapy and photothermal therapy. The possible use of Ru(II) complexes in two-photon photodynamic therapy, photoacoustic imaging and sonotherapy in the future was also discussed. [Display omitted] • Antibacterial studies of Ru(II) photosensitisers with structural modifications. • Advancements in strategies - nanoformulations, combinatory and photothermal therapies. • Future use - two-photon photodynamic therapy, photoacoustic imaging and sonotherapy. [ABSTRACT FROM AUTHOR]

We synthesized a dextrin (DEX)-conjugated graphene oxide (GO) nanocarrier (GO 100 -DEX) as a potential drug delivery system to respond to a tumor-associated stimulus, α-amylase, that has high permeability through the fenestrated endothelial barrier to the tumor site. At acidic pH and in the presence of α-amylase to simulate tumor conditions, GO 100 -DEX released a 1.5-fold higher amount of doxorubicin (DOX) than of GO 100 . Under the same conditions, the cytotoxic effects of GO 100 -DEX/DOX were 2-fold greater than those of free DOX and 2.9-fold greater than those of GO 100 /DOX. Employing an in vitro biomimetic microfluidic blood vessel model lined with human umbilical vein endothelial cells, we evaluated the tumor vasculature endothelial permeation of GO 100 -DEX and GO 100 using dextrans of 10 and 70 kDa for comparison and as standards to validate the microfluidic blood vessel model. The results showed that the permeabilities of GO 100 -DEX and GO 100 were 4.3- and 4.9-fold greater than that of 70 kDa dextran and 2.7- and 3.1-fold higher than that of 10 kDa dextran, thus demonstrating the good permeability of the GO-based nanocarrier through the fenestrated endothelial barrier. [ABSTRACT FROM AUTHOR]

This study reports the in vivo performance of two tribenzyltin carboxylate complexes, tri(4-fluorobenzyl)tin[(N,N -diisopropylcarbamothioyl)sulfanyl]acetate (C1) and tribenzyltin isonicotinate (C9), in their native form as well as in a poly(lactic- co -glycolic acid) (PLGA)-based nanoformulation, to assess their potential to be translated into clinically useful agents. In a 4T1 murine metastatic mammary tumour model, single intravenous administration of C1 (2.7 mg/kg) and C9 (2.1 mg/kg; 2.1 mg/kg C9 is equivalent to 2.7 mg/kg C1) induced greater tumour growth delay than cisplatin and doxorubicin at equivalent doses, while a double-dose regimen demonstrated a much greater tumour growth delay than the single-dose treated groups. To improve the efficacy of the complexes in vivo , C1 and C9 were further integrated into PLGA nanoparticles to yield nanosized PLGA- C1 (183.7 ± 0.8 nm) and PLGA- C9 (163.2 ± 1.2 nm), respectively. Single intravenous administration of PLGA- C1 (2.7 mg C1 equivalent/kg) and PLGA- C9 (2.1 mg C9 equivalent/kg) induced greater tumour growth delay (33% reduction in the area under curve compared to that of free C1 and C9). Multiple-dose administration of PLGA- C1 (5.4 mg C1 equivalent/kg) and PLGA- C9 (4.2 mg C9 equivalent/kg) induced tumour growth suppression at the end of the study (21.7 and 34.6% reduction relative to the size on day 1 for the double-dose regimen; 73.5 and 79.0% reduction relative to the size on day 1 for the triple-dose regimen, respectively). Such tumour growth suppression was not observed in mice receiving multiple-dose regimens of free C1 and C9. Histopathological analysis revealed that metastasis to the lung and liver was inhibited in mice receiving PLGA- C1 and PLGA- C9. The current study has demonstrated the improved in vivo antitumour efficacies of C1 and C9 compared with conventional chemotherapy drugs and the enhancement of the efficacies of these agents via a robust PLGA-based nanoformulation and multiple-drug administration approach. Image, graphical abstract [ABSTRACT FROM AUTHOR]

[Display omitted] • 45 indolenine-substituted pyrazoles and pyrimido[1,2- b ]indazoles were evaluated. • Preliminary SAR analysis in the inhibition of S. aureus biofilm is presented. • The R 1 -fused benzene ring and R 2 -COOH group are crucial for antibiofilm activity. • A hit compound with MBIC 50 and MBEC 50 values comparable to the positive standards was identified. Staphylococcus aureus is a highly adaptable opportunistic pathogen that can form biofilms and generate persister cells, leading to life-threatening infections that are difficult to treat with antibiotics alone. Therefore, there is a need for an effective S. aureus biofilm inhibitor to combat this public health threat. In this study, a small library of indolenine-substituted pyrazoles and pyrimido[1,2- b ]indazole derivatives were synthesised, of which the hit compound exhibited promising antibiofilm activities against methicillin-susceptible S. aureus (MSSA ATCC 29213) and methicillin-resistant S. aureus (MRSA ATCC 33591) at concentrations significantly lower than the planktonic growth inhibition. The hit compound could prevent biofilm formation and eradicate mature biofilms of MSSA and MRSA, with a minimum biofilm inhibitory concentration (MBIC 50) value as low as 1.56 µg/mL and a minimum biofilm eradication concentration (MBEC 50) value as low as 6.25 µg/mL. The minimum inhibitory concentration (MIC) values of the hit compound against MSSA and MRSA were 50 µg/mL and 25 µg/mL, respectively, while the minimum bactericidal concentration (MBC) values against MSSA and MRSA were > 100 µg/mL. Preliminary structure–activity relationship analysis reveals that the fused benzene ring and COOH group of the hit compound are crucial for the antibiofilm activity. Additionally, the compound was not cytotoxic to human alveolar A549 cells, thus highlighting its potential as a suitable candidate for further development as a S. aureus biofilm inhibitor. [ABSTRACT FROM AUTHOR]

Physiochemical changes, including size, are known to affect gold nanoparticle cellular internalization and treatment efficacy. Here, we report the effect of four sizes of cystine/citric acid-coated confeito-like gold nanoparticles (confeito-AuNPs) (30, 60, 80 and 100 nm) on cellular uptake, intracellular localization and photothermal anticancer treatment efficiency in MDA-MB231 breast cancer cells. Cellular uptake is size dependent with the smallest size of confeito-AuNPs (30 nm) having the highest cellular internalization via clathrin- and caveolae-mediated endocytosis. However, the other three sizes (60, 80 and 100 nm) utilize clathrin-mediated endocytosis for cellular uptake. The intracellular localization of confeito-AuNPs is related to their endocytosis mechanism, where all sizes of confeito-AuNPs were localized highly in the lysosome and mitochondria, while confeito-AuNPs (30 nm) gave the highest localization in the endoplasmic reticulum. Similarly, a size-dependent trend was also observed in in vitro photothermal treatment experiments, with the smallest confeito-AuNPs (30 nm) giving the highest cell killing rate, whereas the largest size of confeito-AuNPs (100 nm) displayed the lowest photothermal efficacy. Its desirable physicochemical characteristics, biocompatible nature and better photothermal efficacy will form the basis for further development of multifunctional confeito-AuNP-based nanotherapeutic applications. [ABSTRACT FROM AUTHOR]

Previously reported amphiphilic diblock copolymer with pendant dendron moieties (P 71 D 3 ) has been further evaluated in tumor-bearing mice as a potential drug carrier. This P 71 D 3 -based micelle of an average diameter of 100 nm was found to be biocompatible, non-toxic and physically stable in colloidal system up to 15 days. It enhanced the in vitro potency of doxorubicin (DOX) in 4T1 breast tumor cells by increasing its uptake, by 3-fold, compared to free DOX. In 4T1 tumor-bearing mice, the tumor growth rate of P 71 D 3 /DOX (2 mg/kg DOX equivalent) treated group was significantly delayed and their tumor volume was significantly reduced by 1.5-fold compared to those treated with free DOX. The biodistribution studies indicated that P 71 D 3 /DOX enhanced accumulation of DOX in tumor by 5- and 2-fold higher than free DOX treated mice at 15 min and 1 h post-administration, respectively. These results suggest that P 71 D 3 micelle is a promising nanocarrier for chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

• Development of AuNRsALG nanosonosensitisers for enhanced SDT of breast cancer. • AuNRsALG showed good biocompatibility and sono-stability. • AuNRsALG produced •OH &1O 2 more effectively than the commercial sonosensitisers. • AuNRsALG exhibited high sonotoxicity in breast cancer cells at nanomolar range. • AuNRsALG induced severe DNA damage and cell apoptosis via mitochondrial pathway. Sonodynamic therapy (SDT) emerges as a promising non-invasive alternative for eradicating malignant tumours. However, its therapeutic efficacy remains limited due to the lack of sonosensitisers with high potency and biosafety. Previously, gold nanorods (AuNRs) have been extensively studied for their applications in photodynamic or photothermal cancer therapy, but their sonosensitising properties are largely unexplored. Here, we reported the applicability of alginate-coated AuNRs (AuNRsALG) with improved biocompatibility profiles as promising nanosonosensitisers for SDT for the first time. AuNRsALG were found stable under ultrasound irradiation (1.0 W/cm2, 5 min) and maintained structural integrity for 3 cycles of irradiation. The exposure of the AuNRsALG to ultrasound irradiation (1.0 W/cm2, 5 min) was shown to enhance the cavitation effect significantly and generate a 3 to 8-fold higher amount of singlet oxygen (1O 2) than other reported commercial titanium dioxide nanosonosensitisers. AuNRsALG exerted dose-dependent sonotoxicity on human MDA-MB-231 breast cancer cells in vitro , with ∼ 81% cancer cell killing efficacy at a sub-nanomolar level (IC 50 was 0.68 nM) predominantly through apoptosis. The protein expression analysis showed significant DNA damage and downregulation of anti-apoptotic Bcl-2, suggesting AuNRsALG induced cell death through the mitochondrial pathway. The addition of mannitol, a reactive oxygen species (ROS) scavenger, inhibited cancer-killing effect of AuNRsALG-mediated SDT, further verifying that the sonotoxicity of AuNRsALG is driven by the production of ROS. Overall, these results highlight the potential application of AuNRsALG as an effective nanosonosensitising agent in clinical settings. [ABSTRACT FROM AUTHOR]

• Active targeted aza-BODIPY conjugates are promising photosensitizers for melanoma. • Ex vivo biodistribution assay showed conjugates 1a and 1b accumulated in the tumour. • 1b was found to reduce tumour volume and growth suppression after PDT up to 12 days. Active targeting compound, a non-iodinated derivative of IK-IK-I 2 -azaBODIPY (1a) was previously reported to preferentially bind melanoma over healthy cells. In this study, we evaluate the photodynamic therapy (PDT) efficiency on melanoma cells of 1a , together with its reversed sequence compound KI-KI-I 2 -azaBODIPY (1b) and a non-targeted control I 2 -azaBODIPY-NH 2 (2). All three test compounds possess absorption wavelengths in the near-infrared (NIR) region (λ max between 678 and 687 nm) which alleviate melanin interference and allow deeper tissue penetration. In vitro studies revealed 1a and 1b are promising photosensitizers with enhanced singlet oxygen generation, have increased uptake by B16-F10 melanoma cells via clathrin-mediated endocytosis and good photocytotoxic efficacies. Ex vivo biodistribution assays showed both 1a and 1 b accumulated in the tumour. In B16-F10 tumour bearing-C57BL/6 mice, 10 mg/kg of 1b and light irradiation was found to reduce tumour volume by up to 23% at day-3. Doubling the dosage of 1b (20 mg/kg) enhanced the antitumour effect, showing 96% maximum tumour volume reduction at day-7 and tumour growth suppression for up to 12 days. [ABSTRACT FROM AUTHOR]