Stabilization and acoustic activation of polymeric micelles...

Details Stabilization and acoustic activation of polymeric micelles... Stabilization and acoustic activation of polymeric micelles...

2002-08-07

2003-11-18

Nutter, Nathan M. (Department: 1711)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Mixing of two or more solid polymers; mixing of solid...

C525S280000, C525S284000, C525S327300, C523S201000, C524S504000, C524S505000, C424S486000, C424S487000, C424S489000

Reexamination Certificate

active

06649702

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to stabilization of micelles, and activation of micelles for delivery of substances such as drugs.
BACKGROUND OF THE INVENTION
The efficacy of cancer chemotherapy is limited by toxic side effects of anticancer drugs. The ideal scenario would be to sequester the drug in a package that would have minimal interaction with healthy cells, then at the appropriate time, release the drug from the sequestering container at the tumor site. To achieve this goal, various long-circulating colloid drug delivery systems have been designed during the last three decades. A common structural motif of all these long circulating systems, whether they be nanoparticles, liposomes, or micelles, is the presence of poly(ethylene oxide) (PEO) at their surfaces. The dynamic PEO chains prevent particle opsonization and render them “unrecognizable” by reticulo-endothelial system (RES). [1] This invaluable advantage has promoted extensive research to develop new techniques to coat particles with PEO, techniques ranging from physical adsorption to chemical conjugation.
From the technological perspective, the most attractive drug carriers are polymeric micelles formed by hydrophobic-hydrophilic block copolymers, with the hydrophilic blocks including PEO chains. These micelles have a spherical, core-shell structure, with the hydrophobic block forming the core of the micelle, while the hydrophilic PEO block (or blocks) forms the shell. Block copolymer micelles have promising properties as drug carriers in terms of their size and architecture. The advantages of polymeric micellar drug delivery systems over other types of drug carriers include: 1) long circulation time in blood; 2) appropriate size (10 to 30 nm) to escape renal excretion but to allow for the extravasaation at the tumor site; 3) simplicity in drug incorporation, compared to covalent bonding of the drug to the polymeric carrier and 4) drug delivery independent of drug character. [2]
The ability of PEO-coated particles to prohibit adsorption of proteins and cells depends on the surface density of PEO chains, their length and dynamics. [1,3] However, only a few known block copolymers form micelles in aqueous solutions. Among them, AB-type block copolymers, e.g. poly(L-aminoacid)-block-poly(ethylene oxide) [2,3-13] and ABA-type triblock copolymers. Triblock copolymers of this class are available under the name PLURONIC™, which shall be referred to generically herein as “P-triblock”. P-triblocks are block polymers of PEO and PPO, usually triblock PEO-PPO-PEO copolymers, where PPO stands for poly(propylene oxide); the hydrophobic central PPO blocks form micelle cores, whereas the flanking PEO blocks form the shell, or corona which protects micelles from the recognition by RES. P-triblock copolymers are commercially available from BASF Corp. and ICI. P-triblock polymers are also disclosed in U.S. Pat. No. 5,516,703 to Caldwell et al, issued May 14, 1996, which is hereby incorporated by reference. P-triblock structure in aqueous solution have been extensively investigated by many authors and have been recently reviewed by Alexandridis [22], see also [16]. The phase state of P-triblock micelles can be controlled by choosing members of the P-triblock family with appropriate molecular weight, PPO/PEO block length ratio, and concentration. The hydrodynamic radii of P-triblock micelles at physiological temperatures range between 10 and 20 nm, which makes them prospects as potential drug carriers.
Recently the synthesis of the poly(ethylene oxide-block-isoprene-block-ethylene oxide) triblock copolymer has been reported [23]. Isoprene blocks comprising the core of this copolymer were crosslinked by UV irradiation, rendering micelles stable in the circulation system of mice.
The incorporation of drugs into block copolymer micelles may be achieved through chemical and physical routes. Chemical routes involve covalent coupling of the drug to the hydrophobic block of the copolymer leading to micelle-forming, block copolymer-drug conjugates. However, this approach involved complex synthetic steps and purification procedures. This concept is disclosed in Rigsdorf, et al. [24] and Kataoka, et al. [7-10, 25-27]
Physical entrapment is a better way of loading drugs into micellar systems. Physical entrapment of the anti-cancer drug doxorubicin (DOX) in micelles composed of poly(ethylene oxide-block-b-benzyl L-aspartate) has been disclosed by Kataoka, et. al. [12].
Polymeric surfactants at various aggregation state have been tested as drug carriers. P-triblock molecules in the uniimeric form (below the critical micelle concentration, CMC) were found to sensitize multi-drug resistant (MDR) cancerous cells. Kabanov and Alakhov [20, 28, 29] have found that there is a-dramatic increase in Daunorubicin and DOX cytotoxic activity toward the multi-drug resistant cell lines while in the presence of 0.01 to 1% of PLURONIC P85 or L61. The efficacy of the drug/P-triblock systems dropped above the CMC. It was concluded that the efficacy of P-triblockdelivery systems was based on the presence of P-triblock unimers.
The drop in the efficacy of drug/P-triblock systems above the CMC may be due to the substantial decrease in the intracellular drug uptake from dense P-triblock micelles. [30-32] The drug incorporated into the micelle core is masked from the external media by the corona composed of PEO chains.
This phenomenon may be used advantageously to prevent the unwanted drug interactions with healthy cells. However, the challenge is to ensure drug uptake at the tumor site.
The fundamental difference between using polymeric surfactants below or above the CMC is that below the CMC the enhanced intracellular uptake and enhanced cytotoxicity of the drug delivered with P-triblock unimers is exploited [20, 28, 29, 33], whereas above the CMC, the shielding properties of P-triblock micelles are used to prevent unwanted drug interactions with healthy cells. To ensure drug uptake from (or together with) polymeric micelles at the tumor site, micelle perturbation and cell membrane permeabilization by ultrasound is being proposed [30-32, 34].
Summarizing, drug delivery using micellar drug carriers proved to have many advantages over the use of free drugs.
Some micellar systems are structurally stable (these are micelles with solid-like cores that dissociate slowly at levels below their CMC, e.g. micelles formed by poly(L-aminoacid)-block-poly(ethylene oxide) copolymers [2, 5, 26]). As indicated by NMR data, molecular motion in the core of these micelles is substantially frozen. In contrast, P-triblock micelles or those formed by poly(ethylene oxide-block-isoprene-block-ethylene oxide) triblock copolymer dissociate very fast upon dilution [16]. These micelles have “soft” cores, which means that at room temperature theft molecular segments are above corresponding glass transition temperature, T
g
and move relatively fast. Since upon IV injections, the concentration of the polymeric drug carrier can drop to levels below the CMC, non-stable micelles require additional stabilization to be used in micellar form.
REFERENCES
1. S. I. Jeon, J. H. Lee, J. D. Andrade, p. (3. D. Gennes, J. Colloid Interface Sci. 142-158,(1991) 149-158.
2. K. Kamoka, O. S. Kwon, M. Yokoyarna, T. Okano, Y. Sakurai, I. Control. Release 24, (1993) 119-132.
3. J.-T. Li, K. D. Caldwell, N. Rapoport, Langmuir 10, (1994) 4475-4482.
4. S. Cammas, K. Kataoka, in
Solvents and Self
-
Organization of Polymers
S. E. Webber, Ed. (Kluwer Academic Pubi., Netherland, 1996) pp. 83-113.
5. M. Yokoyama, in Advances in
Polymeric Systems for Drug Delivery
. T. Okano, Ed. (Gordon and Breach Science Publishers, Iverdon, Switzerland, 1994) pp. 24-66.
6. M. Yokoyarna, Polymeric micelles for drug delivery: their stratagy and perspectives., 17th International Symposium on Recent Advantages in Drug Delivery Systems. 1995), pp. 99-102.
7. M. Yokoyama,

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