Trends in Biotechnology
ReviewPoloxamers and poloxamines in nanoparticle engineering and experimental medicine
Section snippets
Long circulating particles
Poloxamers and poloxamines adsorb strongly onto the surface of hydrophobic nanospheres [e.g. polystyrene, poly(lactide-co-glycolide), poly(phosphazene), poly(methyl methacrylate) and poly(butyl 2-cyanoacrylate) nanospheres] via their hydrophobic POP centre block1. This mode of adsorption leaves the hydrophilic POE side-arms in a mobile state because they extend outwards from the particle surface. These side-arms provide stability to the particle suspension by a repulsion effect through a steric
Splenotropic particles
By simple engineering, intravenously injected long circulatory poloxamer- or poloxamine-coated particles can be effectively redirected to sinusoidal spleens (e.g. rat and human). This simply requires a rigid nanosphere in the size range, equivalent to or greater than the reported width of splenic interendothelial cell slits in the sinus walls 2 usually in the order of 200–500 nm (Box 1; Ref. 5).
Conversion of ‘phagocyte-prone’ particles to long-circulatory or splenotropic particles in vivo
Interestingly, intravenously injected, uncoated polystyrene beads (which are cleared rapidly by hepatic Kupffer cells) behaved like long circulatory or splenotropic particles, depending on their size, if they are injected shortly (up to 3 h) after an appropriate dose of poloxamine-908 or poloxamer-407 (Ref. 6). The altered biodistribution profile of the beads is apparently independent of the ‘hepatic-blockade’ concept, which would have been caused by the administered copolymer. Polystyrene
Lymphotropic nanoparticles
One of the most intriguing applications of poloxamer and poloxamine engineered nanoparticles is in the medical imaging of lymphatics, as well as in drug delivery to regional lymph nodes following subcutaneous administration. A correlation was found to exist between the length of the stabilizing POE chains of the block copolymer surfactants, and polystyrene bead (60 nm) drainage from interstitium and passageway across dermal lymphatic capillaries in the rat footpads8. The longer the POE chains
Slow-release gel systems
One particular copolymer, poloxamer-407 exhibits reversible thermal gelation in aqueous solution at concentrations >20% w/v. Therefore, a solution of poloxamer-407 is liquid at low temperatures but rapidly gels at ∼25°C. Such systems have been administered subcutaneously for the slow release of peptides and therapeutic proteins, which include interleukin-2, urease and human growth hormone9., 10., 11.. Following administration, the gels slowly dissolve and release the entrapped protein molecules
Adjuvant activity and vaccine formulation
Several poloxamer and poloxamine copolymers in micellar or aggregate forms have proved to be powerful adjuvants for increasing antibody formation to a variety of antigens following subcutaneous administration14., 15., 16.. Similar results have also been obtained with oil-in-water emulsions stabilized by such copolymers17., 18.. The adjuvant activity of copolymers has been suggested to be influenced by both their size and POE content; maximal activity is reported for copolymers with low POE
Complement activation
Numerous studies have demonstrated that poloxamer and poloxamine copolymers, regardless of their HLB values, can activate the human complement system causing conversion of complement factor 3 (C3) through the alternative pathway18., 23.. Of particular interest is poloxamer-188, which has been used for stabilizing Fluosol-DA, a perfluorocarbon artificial blood substitute emulsion. In a human trial, the copolymer content of Fluosol-DA was responsible for activating the complement system and for
Inhibition of multidrug resistance
A major problem in chemotherapy of many human malignancies is the development of drug resistance25., 26.. Multidrug resistance is the ability of tumour cells to develop resistance to the cytotoxic effects of several chemically unrelated anticancer drugs. This phenomenon has been associated with the overexpression of membrane transport proteins belonging to the superfamily of the ATP-binding cassette25., 26.. Examples include the P-glycoprotein and a newly identified 190–210 kDa
Applications in vascular medicine
Commercial grade poloxamer-188 has been reported to exhibit haemorrheological, antithrombotic and neutrophil-inhibitory properties, presumably via hydrophobic interaction with the surface of blood cells, vascular endothelial cells, and/or alteration of plasma protein properties (particularly fibrinogen, soluble fibrin and albumin)35., 36., 37., 38., 39., 40., 41., 42.. Indeed, poloxamer-188 at a clinically relevant concentration, decreases erythrocyte aggregation, and reduces blood viscosity in
Cell membrane sealing
Several copolymers, such as poloxamer-188 and poloxamine-1107, are capable of sealing electroporated and radiopermeabilized cell membranes in a dose-dependent manner; preventing rapid exhaustion of high-energy cellular compounds and thus resultant cellular necrosis44., 45.. These observations further support the notion that these polymers are ineffective membrane-solubilizing agents and therefore adhere to the cell surface or damaged spots in the membrane. These copolymers might be of potential
A poloxamer for your thoughts
The occurrence of pharmacological and immunological responses in vivo raises several questions that must be addressed regarding the commercially available poloxamers and poloxamines, if they are to be used safely and be amenable to both scientific and clinical rigor. These include:
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What impurities and/or additives are present in commercial polymers, are they immunogenic or do they exhibit pharmacological activity?
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How stable are the polymers to degradative processes once the package is opened?
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Future prospects
Clearly, the purification and characterization of poloxamers and poloxamines for use within the medical and pharmaceutical areas has only undergone a cursory examination. It is imperative that those involved in this field must become aware of the potential hazards lurking within polymer toxicology. This will only be achieved if multidisciplinary groups are formed to tackle the challenges inherent in this work; groups must include immunologists, toxicologists and polymer chemists to add an
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