Chemotherapy of brain tumour using doxorubicin bound to surfactant-coated poly(butyl cyanoacrylate) nanoparticles: Revisiting the role of surfactants

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Abstract

Poly(butyl cyanoacrylate) nanoparticles coated with poloxamer 188 (Pluronic® F68) and also, as shown previously, polysorbate 80 (Tween® 80) considerably enhance the anti-tumour effect of doxorubicin against an intracranial glioblastoma in rats. The investigation of plasma protein adsorption on the surface of the drug-loaded nanoparticles by two-dimensional electrophoresis (2-D PAGE) revealed that both surfactants, besides other plasma components, induced a considerable adsorption of apolipoprotein A-I (ApoA-I). It is hypothesized that delivery of doxorubicin to the brain by means of nanoparticles may be augmented by the interaction of apolipoprotein A-I that is anchored on the surface of the nanoparticles with the scavenger receptor class B type I (SR-BI) located at the blood–brain barrier. This is the first study that shows a correlation between the adsorption of apolipoprotein A-I on the nanoparticle surface and the delivery of the drug across the blood–brain barrier.

Introduction

Efficacy of the chemotherapy of brain pathologies is often impeded by insufficient drug delivery across the blood–brain barrier (BBB), which separates blood from the extracellular fluid in brain parenchyma. In the case of brain tumours, the routine approaches applied for the enhancement of drug concentrations in the brain involve craniotomy-based drug delivery, such as intraventricular drug diffusion or local intracerebral implants, or disruption of the BBB by infusion of hyperosmotic solutions or vasoactive agents prior to systemic administration of the drug. Being highly invasive, these approaches are most appropriate for short-term treatments, where a single or infrequent exposure to a drug is required.

One of the attractive and innovative alternatives is the non-invasive systemic drug delivery to the brain by means of the nanoparticles. For example, as shown by previous extensive studies, poly(butyl cyanoacrylate) (PBCA) nanoparticles coated with polysorbate 80 (Tween® 80) enable the brain delivery of a number of drugs that are unable to cross the BBB in free form [1], [2]. The effectiveness of this drug delivery system was most clearly demonstrated when doxorubicin bound to PBCA nanoparticles coated with polysorbate 80 produced a high anti-tumour effect against an intracranial glioblastoma in rats [3]. It was hypothesized that drug delivery to the brain occurs via receptor-mediated endocytosis of PBCA nanoparticles by the endothelial cells forming the BBB, which was enabled by the ability of polysorbate 80 to selectively promote adsorption of certain plasma proteins (in particular, apolipoproteins E and B) on the surface of these nanoparticles [4], [5]. Indeed, the extensive pharmacological studies demonstrated that binding of dalargin or loperamide to PBCA nanoparticles coated with polysorbate 80 and/or apolipoproteins E and B produced considerable CNS effects (analgesia), whereas the free drugs were not able to cross the BBB and were ineffective [4].

Further studies, however, demonstrated that the mechanism of brain delivery by means of the nanoparticles is more complex. For example, coating of PBCA nanoparticles with other surfactants, such as poloxamer 188 (Pluronic® F68), could also enhance the anti-tumour effect of doxorubicin against intracranial glioblastoma [6]. Moreover, other colloidal carriers such as lipid drug conjugate (LDC) nanoparticles could reach the brain; however, other apolipoproteins – A-I and A-VI – but not apolipoproteins E and B were found on their surface [7].

Taken together, these facts suggest that different particles may deliver drug to the brain by different pathways. Indeed, if the fate of the intravenously administered colloidal carriers is governed by the protein adsorption pattern, then the latter, obviously, depends on the surface properties of the particles and the chemistry of a surface-modifying agent.

The objective of the present study was to gain further insight into the phenomenon of drug delivery to the brain using surfactant-coated PBCA nanoparticles and the possible mechanisms.

Section snippets

Materials

n-Butyl-2-cyanoacrylate (Sicomet® 6000) was obtained from Sichel-Werke (Hanover, Germany), poloxamer 188 (Pluronic® F68) and polysorbate 80 (Tween® 80) were from Sigma (Steinheim, Germany). Doxorubicin hydrochloride (Dox) was a gift from Sicor (Rho, Italy). All chemicals used for 2D-PAGE were of analytical grade and were purchased from Sigma (Steinheim, Germany).

Preparation of doxorubicin-loaded poly(butyl cyanoacrylate) nanoparticles

Poly(butyl cyanoacrylate) (DOX-PBCA) nanoparticles were prepared by anionic emulsion polymerisation: 200 μl of n-butyl-2-cyanoacrylate

Characterization of nanoparticles

In the present study, loading of doxorubicin (Dox) in poly(butyl cyanoacrylate) (PBCA) nanoparticles was achieved by the emulsion polymerization of n-butyl-2-cyanoacrylate in the presence of Dox. Two different stabilizers were used — dextran and poloxamer 188 (Pluronic® F68) = (F68). As shown in Table 1, both procedures yielded nanoparticles of a similar size. Dextran-stabilized nanoparticles exhibited a higher polydispersity and a less negative surface charge and enabled ~ 30% higher loading of

Discussion

The mechanism(s) of the drug transport to the brain by means of the nanoparticles presently is not fully elucidated. A high efficacy of doxorubicin bound to PBCA nanoparticles coated with surfactants in a brain tumour model was evidenced in the studies of Steiniger et al. [3] and Ambruosi et al. [6]. The observed high efficacy clearly indicated that surfactant-coated nanoparticles were able to deliver therapeutic amounts of the drug to the tumour site. However, the role of surfactants appears

Conclusions

The present investigation indicates that the delivery of doxorubicin to the brain by means of PBCA nanoparticles coated with poloxamer 188 and polysorbate 80 may be augmented by the interaction of apolipoprotein A-I adsorbed on the surface of the nanoparticles in plasma with the scavenger receptor SR-BI located at the BBB. This is the first study that shows a significant correlation between the adsorption of ApoA-I on the nanoparticle surface and the delivery of the drug across the BBB.

The

Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (grants 436 RUS 17/1/04 and 436 RUS 17/14/04) and by INTAS (grant 00-838). It also was enabled by a generous gift of doxorubicin by the Sicor Company, Rho, Italy.

References (30)

  • I. Brigger et al.

    Negative preclinical results with stealth® nanospheres-encapsulated doxorubicin in an orthotopic murine brain tumor model

    J. Control. Release

    (2004)
  • S.C. Steiniger et al.

    Chemotherapy of glioblastoma in rats using doxorubicin-loaded nanoparticles

    Int. J. Cancer

    (2004)
  • J. Kreuter et al.

    Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood–brain barrier

    J. Drug Target.

    (2002)
  • J. Kreuter et al.

    Direct evidence that polysorbate-80-coated poly(butylcyanoacrylate) nanoparticles deliver drugs to the CNS via specific mechanisms requiring prior binding of drug to the nanoparticles

    Pharm. Res.

    (2003)
  • A. Ambruosi et al.

    Antitumor effect of doxorubicin loaded in poly(butyl cyanoacrylate) nanoparticles in rat glioma model: influence of formulation parameters

    J. Microencapsulation

    (2006)
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