Blood–Brain-Barrier-Penetrating Albumin Nanoparticles for Biomimetic Drug Delivery via Albumin-Binding Protein Pathways for Antiglioma Therapy

Abstract

Nutrient transporters have been explored for biomimetic delivery targeting the brain. The albumin-binding proteins (e.g., SPARC and gp60) are overexpressed in many tumors for transport of albumin as an amino acid and an energy source for fast-growing cancer cells. However, their application in brain delivery has rarely been investigated. In this work, SPARC and gp60 overexpression was found on glioma and tumor vessel endothelium; therefore, such pathways were explored for use in brain-targeting biomimetic delivery. We developed a green method for blood-brain barrier (BBB)-penetrating albumin nanoparticle synthesis, with the capacity to coencapsulate different drugs and no need for cross-linkers. The hydrophobic drugs (i.e., paclitaxel and fenretinide) yield synergistic effects to induce albumin self-assembly, forming dual drug-loaded nanoparticles. The albumin nanoparticles can penetrate the BBB and target glioma cells via the mechanisms of SPARC- and gp60-mediated biomimetic transport. Importantly, by modification with the cell-penetrating peptide LMWP, the albumin nanoparticles display enhanced BBB penetration, intratumoral infiltration, and cellular uptake. The LMWP-modified nanoparticles exhibited improved treatment outcomes in both subcutaneous and intracranial glioma models, with reduced toxic side effects. The therapeutic mechanisms were associated with induction of apoptosis, antiangiogenesis, and tumor immune microenvironment regulation. It provides a facile method for dual drug-loaded albumin nanoparticle preparation and a promising avenue for biomimetic delivery targeting the brain tumor based on combination therapy.

Chitosan/biphasic calcium phosphate scaffolds functionalized with BMP‐2‐encapsulated nanoparticles and RGD for bone regeneration

“…Furthermore, BMP‐2 can easily be deactivated by enzymes and other physical/chemical reactions . A recent study demonstrated the advantages of serum albumin (human and bovine) nanoparticles as drug carriers, such as biocompatibility and biodegradability . Zhao et al prepared paclitaxel‐loaded bovine serum albumin nanoparticles via a desolvation procedure and achieved the drug entrapment and loading efficiency of 95.3% and 27.2%, respectively.…”

Roles of Albumin‐Binding Proteins in Cancer Progression and Biomimetic Targeted Drug Delivery

“…Other studies also demonstrated that SPARC facilitated glioma cell invasion, and promoted glioma progression by mediating cell survival through AKT activation . We previously reported that SPARC was overexpressed in U87 orthotopic glioma tissues, and interestingly, SPARC expression decreased after treatment with brain‐targeting nanoparticles (NPs) co‐encapsulating paclitaxel (PTX) and fenretinide (4‐HPR), which suggested its function as a therapeutic indicator.…”

“…It was demonstrated that a high level of caveolin‐1 correlated with enhanced Abraxane sensitivity, and caveolin‐1 could serve as a predictive biomarker for the response to albumin‐based chemotherapy . Our previous study showed that gp60 was abundantly expressed in the tumor, and thus, gp60 was a potential target to achieve albumin‐mediated biomimetic delivery in tumors …”

“…It was reported that the BBB in glioma areas overexpressed ABP (e.g., gp60 and SPARC), which potentially served as the delivery target for albumin NPs. In addition, SPARC was also overexpressed in glioma cells; however, minor expression of ABP was found in normal brain tissues . A previous observation revealed that there was a very low level of ABP on normal BBB capillaries, thereby accounting for poor permeation of native albumin .…”

“…Other than serving as nutrient transporters, their functions are not yet fully understood. Some studies have revealed that ABPs (e.g., SPARC and gp60) could be related to tumor progression and be a therapeutic target for cancer therapy …”