1. Field of the Invention
This invention relates to poly(ethylene glycol)-poly(orthoester), poly(ethylene glycol)-poly(orthoester)-poly(ethylene glycol), and poly(orthoester)-poly(ethylene glycol)-poly(orthoester) block copolymers.
2. Background to the Invention
1. Micellar System for Tumor Targeting
One of the major problems in treating cancer is the difficulty of achieving a sufficient concentration of an anticancer agent in the tumor. This is due to the toxicity, sometimes extreme, of such agents which severely limits the amounts that can be used. However, a major discovery in cancer chemotherapy has been the so-called EPR (enhanced permeation and retention) effect. The EPR effect is based on the observation that tumor vasculature, being newly formed vasculature, has an incompletely formed epithelium and is much more permeable than established older vasculature which is essentially impermeable to large molecules. Further, lymphatic drainage in tumors is very poor thus facilitating retention of anticancer agents delivered to the tumor.
The EPR effect can be used in cancer targeting by using delivery systems containing anticancer drugs that are too large to permeate normal vasculature, but which are small enough to permeate tumor vasculature, and two approaches have been developed. In one approach, a water-soluble polymer is used that contains an anticancer drug chemically bound to the polymer via a hydrolytically labile linkage. Such drug-polymer constructs are injected intravenously and accumulate in the tumors, where they are internalized by the cells via endocytosis and released in the lysosomal compartment of the cell via enzymatic cleavage of the labile bond attaching the drug to the polymer. Two disadvantages of this approach are that, first, nondegradable, water-soluble polymers have been used, and this requires a tedious fractionation of the polymer to assure that the molecular weight of the polymer is below the renal excretion threshold, and, second, the drug must be chemically attached to the polymer, which in effect creates a new drug entity with consequent regulatory hurdles that must be overcome. The use of polymer conjugates in cancer diagnosis and treatment is discussed in R. Duncan et al., "The role of polymer conjugates in the diagnosis and treatment of cancer", S.T.P. Pharma Sciences, 6(4), 237-263 (1996), and an example of an alginate -bioactive agent conjugate is given in Al-Shamkhani et al., U.S. Pat. No. 5,622,718.
An alternate approach has been described. In this approach, an AB or ABA block copolymer is prepared where the B-block is hydrophobic and the A-block is hydrophilic. When such a material is placed in water, it will self-assemble into micelles with a hydrophobic tore and a hydrophilic shell surrounding the core. Such micelles have a diameter of about 100 nm, which is large enough that when they are injected intravenously, the micelles can not leave the normal vasculature, but they are small enough to leave the vasculature within tumors. Further, a 100 nm diameter is too small to be recognized by the reticuloendothelial system, thus enhancing micelle lifetime within the blood stream. Additionally, when the hydrophilic block is poly(ethylene glycol), further enhancement of circulation time is noted, as has been observed with "stealth" liposomes. The use of block copolymer micelles is reviewed in G. S. Kwon et al., "Block copolymer micelles as long-circulating drug delivery vehicles", Adv. Drug Delivery Rev., 16, 295-309 (1995).
Sakurai et al., U.S. Pat. Nos. 5,412,072 and 5,693,751, and Yokoyama et al., U.S. Pat. Nos. 5,449,513 and 5,510,103, describe block copolymers useful as micellar delivery systems where the hydrophilic block is poly(ethylene glycol) and the hydrophobic blocks are various derivatives of poly(aspartic acid), poly(glutamic acid) and polylysine. U.S. Pat. Nos. 5,412,072 and 5,693,751 describe an approach where drugs have been chemically attached to the hydrophobic segment; while U.S. Pat. Nos. 5,449,513 and 5,510,103 describe an approach where hydrophobic drugs have been physically entrapped within the hydrophobic portion of the micelle. This latter approach is clearly preferable because no chemical modification of the drug is necessary.
2. Bioerodible Block Copolymer Matrix for Controlled Drug Delivery
In AB, ABA, or BAB block copolymers comprising a hydrophilic A block and a hydrophobic B block, the A and B blocks are incompatible and on a microscopic scale will phase-separate. This phase separation imparts unique and useful thermal properties to the material.
There is considerable prior art in the development of block copolymers comprised of poly(ethylene glycol) and bioerodible hydrophobic segments such as poly(L-lactic acid), poly(L-lactic-co-glycolic acid) copolymers and poly(.epsilon.-caprolactone), and discussion of their use as drug delivery agents. For example, see W. N. E. Wolthuis et al., "Synthesis and characterization of poly(ethylene glycol) poly-L-lactide block copolymers", Third European Symposium on Controlled Drug Delivery, 271-276 (1994), L. Youxin et al., "Synthesis and properties of biodegradable ABA triblock copolymers . . . ", J. Controlled Release, 27, 247-257 (1993), and Bezwada et al., U.S. Pat. No. 5,133,739.
Poly(orthoesters) are known as potential vehicles for sustained release drug delivery. See, for example, J. Heller, "Poly (Ortho Esters)", Adv. Polymer Sci., 107, 41-92 (1993), and references cited therein, Heller et al., U.S. Pat. Nos. 4,304,767, 4,946,931, and 4,957,998, and PCT International Publication No. WO97/25366.
The disclosures of these and other documents referred to in this application are incorporated herein by reference.
However, no block copolymer systems have been described where the hydrophobic, bioerodible segment is a poly(orthoester).