Human serum albumin (HSA) is a vital protein in human plasma, exhibiting reversible binding capabilities with endogenous and exogenous substances. Its unique properties, including biocompatibility, biodegradability, and ability to transport substances to targeted tissues, make it an attractive candidate for drug delivery systems. With the rapid development of nanotechnology, HSA-based nano-drug delivery systems (HBNDSs) have emerged as promising platforms for various biomedical applications beyond cancer therapy.
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Structure and Properties of HSA
HSA synthesized by liver parenchymal cells, comprises 585 amino acid residues with a molecular weight of 66,500 Da. Despite its low content of aromatic amino acids, possessing only one tryptophan, HSA contains numerous amino acids with carboxyl and amino groups, contributing to its exceptional solubility and stability. Notably, HSA maintains remarkable stability over a wide pH range (pH 4-9) and shows excellent tolerance to specific organic solvents, enduring concentrations of up to 40% ethanol and high temperatures of 60°C for 10 hours without denaturation. These properties enable HSA to retain its structural integrity under harsh processing conditions.
Fig. 1 The structure of HSA (Li C., et al. 2023).
HSA consists of three homologous domains (I, II, and III), each further divided into subdomains A and B. These subdomains, composed of six helical structures, form pocket-like structures due to hydrophobic and positively charged groups, creating an advantageous spatial environment for encapsulating hydrophobic molecules. As a natural carrier for hydrophobic substances in the body, HSA's unique spatial structure facilitates binding with a wide range of substances. Two major binding sites, Sudlow site I in subdomain IIA and Sudlow site II in subdomain IIIA, exhibit high affinity for various molecules, including small-molecule drugs, peptides, and nucleic acids. Additionally, HSA possesses four metal binding sites-N-terminal binding site (NTS), cysteine 34 (cys34), and metal binding sites (MBS-A) and MBS-B-allowing the binding of different metal ions.
HSA-Based Multifunctional Nanocarrier
Human serum albumin-based nanodrug delivery systems (HBNDSs) have emerged as versatile platforms for biomedical applications due to their excellent biocompatibility, non-toxicity, non-immunogenicity, and prolonged circulation time. These systems serve as crucial carriers for delivering a wide array of therapeutic drugs, including small-molecule drugs, inorganic materials, and bioactive ingredients, thereby enhancing both imaging performance and therapeutic efficacy across various diseases.
Small-Molecule Drugs
The unique attributes of HSA make it an ideal carrier for small-molecule drugs, offering advantages such as biocompatibility, high drug-loading capacity, prolonged circulation time, and stability. Covalent and non-covalent binding strategies are employed to load small-molecule drugs onto HSA nanoparticles, ensuring controlled release and enhanced therapeutic efficacy. Recent advancements include the development of hypoxia-sensitive nanoparticles for targeted drug delivery to tumor tissues, as well as pH-responsive systems for controlled release in specific microenvironments. Examples of innovative HSA-based nanocarriers, such as HSA-Pt (IV) prodrug conjugates for cancer therapy and ROS-responsive nanoplatforms for combined photo-immunotherapy, demonstrate the potential of these systems in improving treatment outcomes.
Inorganic Materials
The unique binding sites within HSA allow for the synthesis of inorganic metal nanomaterials, including silver sulfide, gadolinium oxide, manganese dioxide, and copper sulfide, through biomimetic biomineralization processes. These inorganic materials exhibit diverse functionalities, such as photothermal conversion and chemodynamic therapy, making them promising candidates for cancer therapy. Additionally, HSA can serve as a template for the covalent linkage of specific inorganic non-metallic nanoparticles, enabling targeted delivery and enhanced therapeutic efficacy. Examples include NIR-II laser-mediated photothermal Fenton nanocatalysts and multifunctional nanoparticles for Alzheimer's disease diagnosis and treatment, showcasing the versatility of HSA-based nanocarriers in biomedical applications.
Bioactive Ingredients
HSA nanoparticles offer a promising platform for delivering bioactive ingredients, including nucleic acids, antibodies, peptides, cytokines, and enzymes, with enhanced stability and systemic circulation. Recent studies have explored the use of HSA-based nanocarriers for delivering therapeutic agents targeting hematological malignancies, autoimmune diseases, and inflammatory disorders. Strategies such as siRNA delivery for gene silencing in leukemia cells and co-loading of anti-rheumatoid arthritis medication with ROS scavengers demonstrate the potential of HSA nanoparticles in personalized medicine and targeted therapy.
The Binding of HSA and Drugs
Covalent Binding
Covalent binding involves linking drugs with human serum albumin (HSA) through chemical addition reactions, exploiting abundant functional groups on HSA such as carboxyl, thiol, and amino groups. This method offers stability and controlled drug release, crucial for targeted therapy. Examples include methotrexate and doxorubicin nanoconjugates. pH-sensitive linkers and enzyme-responsive systems enable precise drug release in tumor microenvironments. For instance, a system combining a photosensitizer with an enzyme-sensitive peptide achieves controlled drug release for photodynamic therapy. Additionally, exploiting hypoxia in tumors, researchers developed hypoxia-sensitive nanoparticles that disintegrate in hypoxic conditions, enhancing deep tissue penetration and treatment efficacy.
Non-Covalent Binding
Non-covalent binding utilizes HSA's inherent binding sites to form drug-HSA complexes or involves encapsulating drugs within HSA nanoparticles. These methods rely on reversible binding interactions like hydrogen bonding and hydrophobic interactions. Such nanoparticles demonstrate versatility and are applicable to various small-molecule drugs. Smart nanoplatforms for cancer therapy, combining photoacoustic imaging, sonodynamic therapy, and chemotherapy, have been developed. Nanoparticles can be engineered to enhance drug targeting by modifying HSA with active ligands like peptides or enzymes. Microenvironment-sensitive nanoparticles respond to disease conditions like pH or enzyme levels, enabling controlled drug release and minimizing toxicity to normal tissues. Studies have shown the effectiveness of albumin-binding molecules in targeting tumors, with reversible and multivalent affinities enhancing pharmacokinetics and tumor-targeting efficiency. Overall, both covalent and non-covalent binding strategies harness the unique properties of HSA for efficient drug delivery and enhanced cancer therapy.
Conclusions
HSA holds promise in drug delivery due to its biocompatibility, safety, and long-lasting nature. Through nanotechnology, drugs can be efficiently coupled with or encapsulated within HSA nanoparticles, improving drug stability, pharmacokinetics, and efficacy while minimizing side effects. Functional groups on HSA enable targeted drug delivery, responsive to specific environmental cues. Notably, HSA-based systems show potential in targeting tumors and inflammatory sites. However, challenges remain, including understanding nanoparticle targeting in diverse diseases, and the role of HSA-binding proteins in nanoparticle uptake. Overcoming limitations such as cost and sourcing, possibly through recombinant HSA, will be crucial for clinical translation. Continued research promises innovative HSA-based therapies and diagnostics for future medical advancements.
Reference
- Li C., et al. Human serum albumin based nanodrug delivery systems: recent advances and future perspective. Polymers. 2023, 15(16): 3354.
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