Introduction:
Nanocarriers are designed to encapsulate and deliver drugs to tumour sites with greater precision, reducing systemic toxicity and improving the therapeutic efficacy of cancer treatments. Albumin is an interesting candidate for nanodrug delivery as it’s the most abundant plasma protein and has low toxicity and immunogenicity profile. It’s a natural nanodelivery system with high binding capacities for both hydrophobic and hydrophilic molecules. The long plasma half-life of albumin is because of the cellular receptor FcRn, which protects the protein from intracellular degradation. Due to its chemical structure and presence of different functional group, there are more opportunities for modifying the surface of the particle through non-covalent and covalent bonding, allowing them to be used for different drug targets.
Drug Binding and Albumin Nanoparticle Formation:
Albumin's abundant functional residues and diverse secondary structures offer versatile drug-binding possibilities (Fig.1). Two main binding methods are employed:
Non-covalent Binding; leverages albumin's secondary structures for reversible drug attachment via ionic or hydrophobic interactions. Albumin's substructures, Sudlow site I and II, are essential for drug-albumin interactions, offering specific binding pockets for different drugs.
Covalent binding involves the formation of strong, permanent chemical bonds between the drug and albumin. While this method is less common than non-covalent binding, it can be used to create stable drug-albumin conjugates. These covalent bonds can enhance drug stability and prolong drug circulation time in the body.
There are several different techniques that can be used to prepare albumin NPs, including desolvation (Fig.2a), emulsification (Fig.2b), self-assembly (Fig.2c) thermal gelation (Fig.2d), nanospray drying (Fig.2e) and ‘Nab-technology,
Albumin for Drug Delivery in Cancerous Tumours:
Solid cancerous tumours often exhibit an enhanced permeation and retention (EPR) effect, characterized by leaky blood vessels and poor lymph drainage. This EPR effect passively guides many nanocarriers into tumour sites. By using vascular dilators like nitric oxide (NO) to enhance blood vessel permeability through vasodilation, the EPR effect can be boosted to overcome insufficient drug accumulation in tumours. Combining an albumin-based drug delivery system with S-nitrosated HSA dimer (SNO-HSA) enhances passive targeting and significantly improves tumour suppression compared to using the drug delivery system alone.
Albumin has a unique property of binding to receptors overexpressed by tumours, primarily via receptor-mediated endothelial transcytosis. Albumin binds tightly to the Gp60 receptor found on tumour endothelial cells, triggering invagination of the cell membrane and the formation of transcytosis vesicles (caveolae) for transporting albumin into the tumour. Additionally, the presence of SPARC (secreted protein acidic rich in cysteine) in many tumour types, absent in normal tissues, attracts albumin, further contributing to its accumulation in tumours. These mechanisms allow albumin to actively target cancer cells, as Gp60 is overexpressed on these cells, facilitating transport across biological barriers.
The FcRn receptor plays a crucial role in maintaining high albumin levels by recycling internalized albumin back into the bloodstream through a pH-dependent mechanism.
Gp18 and Gp30 are scavenger proteins that preferentially bind to old, damaged, and altered albumin, not native albumin. These receptors are responsible for the degradation of modified albumins.
To improve albumin's active targeting capacity, its nanoparticle surface can be modified with specific agents like antibodies, peptides, folic acid, and aptamers, enhancing precision and reducing immunogenicity.
Conclusion:
Albumin-based nanocarriers hold great promise for enhancing drug delivery in cancer therapy. Their ability to encapsulate a wide range of drugs, coupled with albumin's natural affinity for tumour sites and versatile modification options, makes them a valuable tool in the fight against cancer. By leveraging the EPR effect and active targeting mechanisms, these nanocarriers are poised to improve the precision, efficacy, and safety of cancer treatments.
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-By Riya Gurav
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