How does albumin bound paclitaxel cross cell membranes?

Mechanism of Cell Membrane Crossing

Albumin-bound paclitaxel, also known as nanoparticle albumin-bound (NAB) paclitaxel, utilizes a unique mechanism to cross cell membranes [1]. Unlike traditional solvent-based formulations, NAB paclitaxel relies on the binding of paclitaxel to human serum albumin (HSA), a naturally occurring protein in the bloodstream [2].

Role of Human Serum Albumin

HSA serves as a carrier for paclitaxel, encapsulating it in a complex that is 130-140 nm in diameter. This larger size allows the complex to evade rapid renal excretion, prolonging systemic exposure and increasing tumor targeting. Furthermore, the HSA-paclitaxel complex is more stable than free paclitaxel, which degrades rapidly in solution [2].

Endocytic Uptake

The HSA-paclitaxel complex is taken up by cells via endocytic pathways, including macropinocytosis and caveolar-mediated endocytosis [3]. Once internalized, the complex is delivered to endosomes, where paclitaxel is released from the albumin carrier due to changes in pH and proteolytic activity [4].

Release of Paclitaxel

Paclitaxel is then released from the endosomal compartment into the cytoplasm, where it can access the mitotic spindle and exert its anticancer effects. The release of paclitaxel into the cytoplasm is facilitated by the low pH and high proteolytic activity within endosomes, which disrupt the HSA-paclitaxel complex [4].

Comparison to Traditional Formulations

In contrast to traditional solvent-based paclitaxel formulations, which rely on passive diffusion across cell membranes, NAB paclitaxel utilizes endocytic pathways to deliver paclitaxel to the cytoplasm. This targeted delivery mechanism increases the efficacy and reduces the toxicity of paclitaxel compared to traditional formulations [5].

References:
[1] https://drugpatentwatch.com/patent/USA-PCT/2013/051441/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391447/
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335115/
[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441117/
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401114/

Sources:

1. USA-PCT/2013/051441
2. PMC4391447
3. PMC4335115
4. PMC4441117
5. PMC4401114