PEGs, acid-sensitive

With the aim to reduce unspecific protein interactions while controlling DNA release, acid-sensitive PEG has been designed. Several pH-sensitive systems are described in Volume I, Chapter 8. Briefly, the objective is to develop molecules for biological purposes, which means molecules able to be destabilized at slight pH changes. Tumors or ischemia sites present... 

Acid-sensitive cholesterol PEG as well as acid-sensitive Brij compounds have been synthesized and incorporated into lipoplexes (Fig. 5) (41). Different orthoester linkages incorporated within the PEG-lipid spacer allowed different sensitivity of the molecule to pH. The orthoester group (42) is advantageous not only because of its sensitivity to pH changes but also because... 

As expected, acid-labile PEG did not increase the circulation time of the lipoplexes as compared to PEGylated lipoplexes but allowed for the same level to be reached, indicating the stability of the acid-sensitive PEG-lipid moiety in the blood. 

The second limitation, however, remains i.e., lipoplex stabilization, which prevents DNA release. A combination of solutions should be envisioned for further improvement. For instance, we could combine the postgrafting method with exchangeable PEG. We indeed combined the use of acid-sensitive PEG-lipid and the postgrafting method. Results tend to show an improved DNA release cumulated with higher circulation time (unpublished). However, the differences in tumor growth and vascularization render difficult the obten-tion of significant and reproducible results. 

EDC FDPP Fmoc HOBt LiHMDS MAMP MCPBA MeOPEG NCA NMP PAL PASP PBP PEG SASRIN TEA TFA TMAD N-Ethyl-N - [ 3 - (dimethy lamino)propy 1] -c arbodiimide hydrochloride Pentafluoro phenyldiphenyl phosphate 9 -Fluoreny lme thoxy c arbony 1 Hydroxybenzotriazol Lithium hexamethyldisilazane Merrifield, alpha methoxy phenyl resin w-Chloroperbenzoic acid Methoxy polyethylene glycol /V-Carboxv a-aminoacid anhydride /V - M e t h v 1 pyrrol i do n e Peptide amide linker Polymer assisted solution phase Penicillin-binding proteins Polyethylene glycol Super acid sensitive resin Triethylamine Trifluoroacetic acid Tetramethylamine azodicarboxylate. 

Acid-sensitive PEG-DOX was prepared to control drug release in endosomes and lysosomes within tumor cellsJ l... 

GV 0.6% amino acid composition Gly 1.06, Ala 0.96, Val 1.03, Leu 0.96. In a similar study, PEG-PS and PS were loaded with 2,4,5-trichlorophenyl-3 -[4"-(N -Fmoc-valyloxymethyl)phenoxy]propionate Fmoc removal was with piperidine-CH2Cl2 (1 1) (2 + 10 min), and 3-h couplings of appropriate Fmoc-amino acids (3 equiv.) were mediated by DCC-HOBt (3 equiv.) in CH2CI2 (minimal DMF added for solubility). Completed peptide resins were treated to remove Fmoc, and cleaved with TFA-CH2CI2 (1 1) (3 ml) for 1 h, yields > 98% in both cases, due to the more acid-sensitive handle used (PAB ester, 2C spacer). From PEG-PS, the distribution of peptides was LAGV 98.9%, AGV 0.5%, LAV 0.3%, LGV 0.2%, GV... 

Whatever the chemistry, MALDI mass spectrometry has proved to be very effective in validating results of synthesis performed on PEG. Nevertheless some drawbacks were spotted. First, a chemical reactivity directed by the acidic properties of the matrix co-crystallized with the sample under investigation was observed with acid-sensitive Schiff bases. The side reaction was avoided when a nonacidic matrix (2,4,6-trihydroxyacetophenone) was used. Second, mixture analysis was quite difficult to conduct due to the presence of large overlapping distributions. For these two reasons ESI mass spectrometry was also investigated to monitor PEG-mediated syntheses as it requires no specific sample treatment prior to analysis and is easily coupled to a liquid chromatography to profile mixtures. 

TentaGel-N, linked via the succinoyl linker to a monosaccharide acceptor was utilized using trichloroacetimidate chemistry to prepare disaccharides [34] and trisaccharides [78]. It was observed that TentaGel is slightly unstable under the acidic conditions required by trichloroacetimidate chemistry [78], most likely due to the acid sensitivity of PEG [79]. No similar sensitivity was observed in similar applications employing Argogel [78]. 

Zhu and co-workers made an attempt to incorporate acid-sensitive c/s-aconityl linkage between doxorubicin and PAMAM to produce PEG-PAMAM c/s-aconityl-DOX (PPCD) conjugate. DOX release from these conjugates followed acid-triggered kinetics [49]. 

Erotic impurities have to be taken into account for two groups of ionic liquids those that have been produced by an exchange reaction involving a strong acid (often the case, for example, for [BMIM][PEg]), and those that are sensitive to hydrolysis. In the latter case, the protons may originate from the hydrolysis of the anion, forming an acid that may be dissolved in the ionic liquid. 

If decomposition of quats in the presence of strong bases becomes too severe, one can switch to other PT catalysts such as PEGs or crown ethers. These are not very sensitive to bases but are sensitive to acids. 

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