Chemistry

PG is usually prepared by removing the benzyl protecting group of poly(g-benzyl-l-glutamate) that is attained by polymerization of g-benzyl-l-glutamate N-carboxyanhydride (NCA) monomer.4

Direct phosgenation of g-benzyl-l-glutamate produces the corresponding NCA monomer.5,6 In this reaction, g-benzyl-l-glutamate is suspended in a dry inert solvent such as ethyl acetate, dioxane, or tetrahydrofuran, and it is allowed to heterogeneously react with the cyclizing reagent that is normally triphosgene. Researchers have used both the protic and aprotic initiators in the polymerization of g-benzyl-l-glutamate NCA monomer.7 Protic initiators such as primary amines are acylated by attack on the 5-position of the NCA, whereas aprotic initiators such as tertiary amines and alkoxides act as general bases. The ring-opening polymerization of NCA initiated by amines usually produces polymers with relatively broad molecular weight distributions. To circumvent this problem, Deming8 developed the zero-valence nickel catalyst bipyNi(COD) (bipy: 2,2'-bipyridyl; COD: 1,5-cyclooctadiene) to initiate polymerization of NCAs. The active sites derived with this initiator are less accessible to side reactions when compared with that derived with amine initiators because of steric and electronic effects, resulting in polymers with a narrow molecular weight distribution (Mw/Mn, 1.05-1.15).

Impurities in NCAs can have a detrimental effect on the reproducibility of polyamino acid synthesis. NCAs are usually subjected to repeat recrystallization to eliminate trace amounts of impurities. A recent report described an efficient method of removal of hydrogen chloride and the hydrochloride salt of unreacted starting amino acids.9 This method consists of extraction of NCA solution in ethyl acetate with water and an aqueous alkali solution at 0°C. Using highly purified monomer NCAs, Aliferis et al.10 were able to achieve living polymerization initiated with primary amine initiators. This technique produced poly(g-benzyl-l-glutamate) with an average molecular weight as high as 1.66 X105 Da and with a relatively narrow molecular weight distribution (Mw/ Mn, 1.40).

The benzyl protecting group in poly(g-benzyl-l-glutamate) is removed by treatment with hydrogen bromide. Researchers have also used alkaline hydrolysis of poly(l-methyl glutamate) to prepare PG; however, racemization occurred during this process.11 To avoid using harsh conditions for the removal of protecting groups, investigators have prepared glutamic acid NCAs having ester protecting groups that are labile under mild acidic conditions. For example, PG can be readily obtained from poly(g-piperonyl-l-glutamate) by treating the polymer with trifluoroacetic acid.12

PG-based block copolymers can be prepared using macroinitiators or polymer coupling reactions. The block copolymer PG-vinylsulfone-polyethylene glycol (PEG) was prepared by directly reacting a heterofunctional PEG, vinylsulfone-PEG-N-hydroxysuccinimide (NHS), with an amino group at one end of the PG chain.13 Also, Nishiyama et al.14 used the macroinitiator PEG-NH2 to initiate polymerization of g-benzyl-l-glutamate NCA to produce a PEG-PG block copolymer.

Another polymer derived from poly(g-benzyl-l-glutamate) is poly(hydroxyethylglutamate) (PHEG) that is also a suitable candidate drug carrier.15 PHEG is a water-soluble, neutral polymer that can be readily prepared from poly(g-benzyl glutamate) via aminolysis with 2-aminoethanol using 2-hydroxypyridine as a catalyst.16

The linkage of polymer-drug conjugates is important to the in vivo release of a drug that should be stable during circulation but should also allow drug release at an appropriate rate at the tumor tissue.17 Generally, two kinds of linkage are involved in anti-cancer drug delivery by using polymer-drug conjugates: enzymatic hydrolysis and nonenzymatic hydrolyzable linkage. Many proteolytic enzymes such as cysteine proteinase cathepsins are expressed on the surface of meta-static tumor cells.18,19 The linker chemistry can be designed in such a way that the active agents would be released from the polymer-drug conjugates only upon exposure to the proteinases in the tumors. Alternatively, hydrolytically labile, pH-sensitive linkages (i.e., hydrozone, ester, acetals, etc.) have exhibited their utility for tumorotropic or lysosomotropic delivery because the microenvironments of solid tumors are known to be acidic.20,21 PG-TXL conjugate releases TXL through both mechanisms: backbone degradation mediated through proteolytic enzymes and side chain hydrolysis of the ester bond formed between glutamic acid and TXL.

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