Human serum albumin binders: A piggyback ride for long-acting therapeutics

Ullah, Aziz; Lim, Sung In

doi:10.1016/j.drudis.2023.103738

Cited by 12 publications

(4 citation statements)

References 117 publications

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“…Hence, endogenous HSA can serve as a valuable carrier for targeted drug delivery to tumors by utilizing albumin-binding moieties, enabling the biomimetic delivery of drugs to tumor cells ( Zhang et al, 2017 ; Rapozzi et al, 2022 ). Several studies have shown that the attachment of drugs or molecular conjugates to HSA significantly prolongs their circulation time and decreases their clearance from the reticuloendothelial system, thus promoting accumulation and retention at the tumor site ( Spada et al, 2021 ; Fan et al, 2022 ; Ullah et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

HSA-nanobinders crafted from bioresponsive prodrugs for combined cancer chemoimmunotherapy–an in vitro exploration

Tubertini,

Menilli,

Milani

et al. 2024

Front. Chem.

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Introduction: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer still lacking effective treatment options. Chemotherapy in combination with immunotherapy can restrict tumor progression and repolarize the tumor microenvironment towards an anti-tumor milieu, improving clinical outcome in TNBC patients. The chemotherapeutic drug paclitaxel has been shown to induce immunogenic cell death (ICD), whereas inhibitors of the indoleamine 2,3- dioxygenase 1 (IDO1) enzyme, whose expression is shared in immune regulatory and tumor cells, have been revealed to enhance the anti-tumor immune response. However, poor bioavailability and pharmacokinetics, off-target effects and hurdles in achieving therapeutic drug concentrations at the target tissue often limit the effectiveness of combination therapies.Methods: This work describes the development of novel biomimetic and carrier-free nanobinders (NBs) loaded with both paclitaxel and the IDO1 inhibitor NLG919 in the form of bioresponsive and biomimetic prodrugs. A fine tuning of the preparation conditions allowed to identify NB@5 as the most suitable nanoformulation in terms of reproducibility, stability and in vitro effectiveness.Results and discussion: Our data show that NB@5 effectively binds to HSA in cell-free experiments, demonstrating its protective role in the controlled release of drugs and suggesting the potential to exploit the protein as the endogenous vehicle for targeted delivery to the tumor site. Our study successfully proves that the drugs encapsulated within the NBs are preferentially released under the altered redox conditions commonly found in the tumor microenvironment, thereby inducing cell death, promoting ICD, and inhibiting IDO1.

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Section: Introductionmentioning

confidence: 99%

HSA-nanobinders crafted from bioresponsive prodrugs for combined cancer chemoimmunotherapy–an in vitro exploration

Tubertini,

Menilli,

Milani

et al. 2024

Front. Chem.

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“…The distinct localization of ozoralizumab to inflamed joints in arthritic model mice was also reported, presumably because albumin preferentially accumulates at sites of inflammmation . Thus, for the purpose of improving the pharmacokinetics of bioactive ingredients, ABMs with various molecular structures have been developed, including small molecules, peptides, and antibody domains. − The favorable pharmacokinetic profiles of ABMs, which are attributable to their molecular size, epitope, thermal stability, and HSA binding affinity, will thus also apply to their appended therapeutics. , …”

Section: Introductionmentioning

confidence: 98%

“…Additionally, HSA conjugation of glucagon-like-peptide 1 significantly extends its serum half-life . Alternatively, therapeutic agents can be genetically or chemically appended to albumin-binding moieties (ABMs) that bind to endogenous HSA upon in vivo administration . Ozoralizumab is a bispecific treatment for rheumatoid arthritis, consisting of two human-TNFα-binding variable domains of heavy chains of heavy-chain antibodies (VHHs) and one HSA-binding VHH .…”

Section: Introductionmentioning

confidence: 99%

Mirror-Image Human Serum Albumin Domain III as a Tool for Analyzing Site II-Dependent Molecular Recognition

Iwamoto,

Kai,

Inuki

et al. 2024

Bioconjugate Chem.

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Human serum albumin (HSA) as a drug carrier can significantly improve the pharmacokinetic profiles of short-lived therapeutics. Conjugation of albumin-binding moieties (ABMs) to therapeutic agents may prolong their serum half-life by promoting their association with endogenous HSA. To discover a new molecular class of ABMs from mirror-image chemical space, a preparation protocol for bioactive HSA domain III and its d-enantiomer (d-HSA domain III) was established. Structural and functional analyses suggested that the synthetic protein enantiomers exhibited mirror-image structures and stereoselective neonatal fragement crystallizable receptor (FcRn) recognition. Additionally, the ligand-binding properties of synthetic l-HSA domain III were comparable with those of site II in native HSA, as confirmed using site II-selective fluorescent probes and an esterase substrate. Synthetic d-HSA domain III is an attractive tool for analyzing the site II-dependent molecular recognition properties of HSA.

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“…With a molecular mass of 66 kDa and a hydrodynamic diameter approximately seven times larger than a small molecule fluorophore [ 31 ], HSA exhibits unique physicochemical and pharmacokinetic properties as well as physiological functions. It circulates in the lymphatic system around 28 times during its lifetime, interacting with receptors and boasting a circulating half-life of approximately 19 days [ 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

HSA-ZW800-PEG for Enhanced Optophysical Stability and Tumor Targeting

Jang,

Ser,

Cardenas

et al. 2023

IJMS

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Small molecule fluorophores often face challenges such as short blood half-life, limited physicochemical and optical stability, and poor pharmacokinetics. To overcome these limitations, we conjugated the zwitterionic near-infrared fluorophore ZW800-PEG to human serum albumin (HSA), creating HSA-ZW800-PEG. This conjugation notably improves chemical, physical, and optical stability under physiological conditions, addressing issues commonly encountered with small molecules in biological applications. Additionally, the high molecular weight and extinction coefficient of HSA-ZW800-PEG enhances biodistribution and tumor targeting through the enhanced permeability and retention effect. The unique distribution and elimination dynamics, along with the significantly extended blood half-life of HSA-ZW800-PEG, contribute to improved tumor targetability in both subcutaneous and orthotopic xenograft tumor-bearing animal models. This modification not only influences the pharmacokinetic profile, affecting retention time and clearance patterns, but also enhances bioavailability for targeting tissues. Our study guides further development and optimization of targeted imaging agents and drug-delivery systems.

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Human serum albumin binders: A piggyback ride for long-acting therapeutics

Cited by 12 publications

References 117 publications

HSA-nanobinders crafted from bioresponsive prodrugs for combined cancer chemoimmunotherapy–an in vitro exploration

HSA-nanobinders crafted from bioresponsive prodrugs for combined cancer chemoimmunotherapy–an in vitro exploration

Mirror-Image Human Serum Albumin Domain III as a Tool for Analyzing Site II-Dependent Molecular Recognition

HSA-ZW800-PEG for Enhanced Optophysical Stability and Tumor Targeting

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