High pressure homogenisation: binding albumin nanoparticles to Paclitaxel
Each individual’s cancer is a result of a unique combination of genetic alterations, and so specifically targeting these cells via anti-cancer therapy proves very challenging. Whilst systemic chemotherapy proves effective in many cases, it is far from “targeted”, often observed by the range of adverse side effects all over the body.
One example drug is Paclitaxel, which is often used to treat cancers of the ovary, breast, lung, pancreas and cervix. Paclitaxel is part of the Taxane group, which is an important class of chemotherapeutics, due to effective anti-tumour characteristics, though their highly hydrophobic nature has somewhat limited their clinical advances.12 To overcome its poor aqueous solubility, Paclitaxel has long been dissolved in Cremophor EL for delivery, although, the downside being its association with severe anaphylactic hypersensitivity reactions, as well as other very adverse side effects, making this a less than adequate solution, in many circumstances.
An alternative to the above has seen industry favour the implementation of high pressure homogenisation (HPH) to remove the requirement for Cremophor EL within the formulation. This has largely been due to R&D data, which suggests HPH helps facilitate the binding of albumin nano-particles to Paclitaxel; producing a drug known as nab-Paclitaxel.
HPH also promotes cross-linking of the albumin coating via disulphide bonds, thus stabilising the nanoparticle, and removing the Cremophor EL requirement.
It was demonstrated that nab-Paclitaxel (ABI-007) is superior to an equitoxic dose of standard Paclitaxel for response rates, with a significantly lower incidence of toxicities in a large, randomised phase III trial.2 Patients receiving second-line or greater therapy nab-Paclitaxel were observed to have longer median survival compared to those treated with Cremophor-EL-Paclitaxel.3
Along with removing adverse effects form Cremophor El exposure, the albumin nanoparticles can target albumin receptors (gp60), and undergo transcytosis through endothelial cells, and target the albumin-binding protein SPARC, which is an over-expressed protein in the majority of tumours.4
The Albumin-binding (illustrated in the photo on the right) also facilitates linear pharmacokinetics, for predictable drug exposure with dose modification.
Optimising the high pressure homogenisation process facilitates smaller particle sizes, which can significantly improve the bioavailability of a product. For example, particles smaller than 250nm avoid identification by macrophages, which remove particles via the reticuloendothelial system.5 Factors which affect resulting particle size include homogenising pressure, sample temperature, the number of passes through the homogeniser and the concentration of particles.
The Avestin range of high pressure homogenisers allow the user ease in optimising the process parameters, via adjustable homogenising pressures of up to 30,000psi, along with available mechanisms of stringent temperature control.
Many cancers still associate with poor prognosis rates. One example is pancreatic cancer, which is often asymptomatic until late in the course of the disease. There is also a lack of specific, cost-effective screening tests that can easily and reliably find early-stage pancreatic cancer in asymptomatic people. Once disease-specific symptoms begin to appear, pancreatic cancer is often at a late stage, and possibly metastatic. If the cancer spreads to a distant part of the body, the five-year survival rate lies at 2%.6
Promising responses have been observed in patients treated with nab-Paclitaxel combined with Gemcitabine, and so the binding of albumin nanoparticles to other chemotherapeutics via high pressure homogenisation, and the potential combination with existing drug formulations, may hold the key to advancing a number of chemotherapeutic treatments.
As highlighted in this article on the Manufacturing Chemist, high pressure homogenisation is also facilitating improved drug delivery via the formation of liposomes, which are becoming widely regarded as effective transport systems, particularly for drugs with poor bioavailability.
For more information on the Avestin range of high pressure homogenisers, visit: firstname.lastname@example.org or call Ashley Morgan (BSc) on +44 (0)1962 841092