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Near-infrared activatable phthalocyanine-poly-L-glutamic acid conjugate: increased cellular uptake and light-dark toxicity ratio toward an effective photodynamic cancer therapy

Kiew LV, Cheah HY, Voon SH, Gallon E, Movellan J, Ng KH, et al.

Nanomedicine, 2017 05;13(4):1447-1458.
PMID: 28214608 DOI: 10.1016/j.nano.2017.02.002

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 λmax675nm 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.

Matched MeSH terms: Glutamic Acid/chemistry*
Structure-interaction-performance relationships in quercetin-based co-amorphous systems: insights from molecular simulations and experimental characterization

Aslam I, Nayak A, Zaman Raja Yahya MF, Khatib I, O'Reilly NJ, Alhajj N

Eur J Pharm Biopharm, 2026 Dec;229:115262.
PMID: 42860229 DOI: 10.1016/j.ejpb.2026.115262

Quercetin (QUE) has recently attracted increasing interest as a co-former in co-amorphous systems owing to its multiple hydrogen-bonding functionalities. However, the relationship between its intermolecular interactions and co-amorphous performance remains poorly understood. This study investigated the influence of co-former chemistry on the molecular interactions, stability, and aqueous performance of quercetin-based co-amorphous systems using arginine (ARG) and glutamic acid (GLU) as model amino acid co-formers. Co-amorphous formulations were prepared by spray drying and characterized using molecular modelling, solution-state 1H NMR titration, FTIR spectroscopy, PXRD, mDSC, dynamic vapour sorption, solubility, and dissolution studies. Molecular simulations predicted stronger miscibility and intermolecular interactions in the QUE-ARG systems than in the corresponding QUE-GLU systems, which was supported by NMR and FTIR analyses. Although all formulations were initially amorphous, the QUE-GLU systems crystallized within one week of storage, whereas the QUE-ARG systems remained amorphous for at least three months. Notably, the QUE-GLU formulations exhibited comparable or higher glass-transition temperatures, indicating that Tg alone was not predictive of physical stability. The stronger interactions observed in the QUE-ARG systems were also associated with substantially improved saturated solubility and dissolution performance. These findings demonstrate that the effectiveness of quercetin as a co-former depends on the nature and specificity of intermolecular interactions and highlight their importance in the rational design of quercetin-based co-amorphous systems.

Matched MeSH terms: Glutamic Acid/chemistry
Fulltext In vitro cellular localization and efficient accumulation of fluorescently tagged biomaterials from monodispersed chitosan nanoparticles for elucidation of controlled release pathways for drug delivery systems

Hassan UA, Hussein MZ, Alitheen NB, Yahya Ariff SA, Masarudin MJ

Int J Nanomedicine, 2018;13:5075-5095.
PMID: 30233174 DOI: 10.2147/IJN.S164843

Background: Inefficient cellular delivery and poor intracellular accumulation are major drawbacks towards achieving favorable therapeutic responses from many therapeutic drugs and biomolecules. To tackle this issue, nanoparticle-mediated delivery vectors have been aptly explored as a promising delivery strategy capable of enhancing the cellular localization of biomolecules and improve their therapeutic efficacies. However, the dynamics of intracellular biomolecule release and accumulation from such nanoparticle systems has currently remained scarcely studied.
Objectives: The objective of this study was to utilize a chitosan-based nanoparticle system as the delivery carrier for glutamic acid, a model for encapsulated biomolecules to visualize the in vitro release and accumulation of the encapsulated glutamic acid from chitosan nanoparticle (CNP) systems.
Methods: CNP was synthesized via ionic gelation routes utilizing tripolyphosphate (TPP) as a cross-linker. In order to track glutamic acid release, the glutamic acid was fluorescently-labeled with fluorescein isothiocyanate prior encapsulation into CNP.
Results: Light Scattering data concluded the successful formation of small-sized and mono-dispersed CNP at a specific volume ratio of chitosan to TPP. Encapsulation of glutamic acid as a model cargo into CNP led to an increase in particle size to >100 nm. The synthesized CNP exhibited spherical shape under Electron Microscopy. The formation of CNP was reflected by the reduction in free amine groups of chitosan following ionic crosslinking reactions. The encapsulation of glutamic acid was further confirmed by Fourier Transform Infrared (FTIR) analysis. Cell viability assay showed 70% cell viability at the maximum concentration of 0.5 mg/mL CS and 0.7 mg/mL TPP used, indicating the low inherent toxicity property of this system. In vitro release study using fluorescently-tagged glutamic acids demonstrated the release and accumulation of the encapsulated glutamic acids at 6 hours post treatment. A significant accumulation was observed at 24 hours and 48 hours later. Flow cytometry data demonstrated a gradual increase in intracellular fluorescence signal from 30 minutes to 48 hours post treatment with fluorescently-labeled glutamic acids encapsulated CNP.
Conclusion: These results therefore suggested the potential of CNP system towards enhancing the intracellular delivery and release of the encapsulated glutamic acids. This CNP system thus may serves as a potential candidate vector capable to improve the therapeutic efficacy for drugs and biomolecules in medical as well as pharmaceutical applications through the enhanced intracellular release and accumulation of the encapsulated cargo.

Matched MeSH terms: Glutamic Acid/chemistry

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