Acid-sensitive spacers

Drugs that have primary amino groups available for conjugation, for instance dopamine and doxorubicin, can in principle be coupled to LMWPs via oligopeptides. In contrast to the carboxypeptidases, the aminopeptidases appear to possess a broader specificity. To allow the release of terminal amino group-containing drugs in the acid environment of the lysosomes without the requirement of enzymes, an acid-sensitive spacer can be used. 

Linker hydrolysis there is presence of acid-labile linkages between the pol5mier and drug in the pol5mier backbone or side-chain. Presence of these acid-sensitive spacers between drug and polymer enables release of drug either in relatively acidic extracellular fluids in a tumor, or after endocytosis in the... 

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... 

Table 3.1 lists the most commonly used types of acid-sensitive benzyl alcohol linker. All these can be attached to various supports by the use of different types of spacer. Because resins bearing these linkers are commercially available, their preparation will not be discussed here. 

TFA in DCM cleaved the peptide acid from the resin whilst retaining tBu/ Boc-based side-chain protection. Riniker [11] later developed a version of this linker with enhanced acid sensitivity by insertion of two extra methylene groups into the linker spacer 4. The Sasrin linker 3, developed by Mergler [10], is also based on the same dialkoxybenzyl alcohol structure, but in this case the linker is attached directly to Merrifield resin via an ether bond. 

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... 

Auer et al. [134] presented an example for multilayer formation and controlled deposition of functionalized nanoparticles on SAM of mercaptohexadecanoic acid (MHA) using electrostatic interactions. As a pH-sensitive switchable linker between the SAM of MHA and negatively charged gold nanoparticles, bis-benzami-dine bolaamphiphiles having different alkyl spacers were used [135]. This strategy resulted in a potentially tunable and switchable property of the entire assembly. For example, the kinetics of adsorption as well as the final particle layer thickness can be controlled by the kind of bis-benzamidine used as the linker (Fig. 9.16). 

The perylene chromophotes were modified by covalently attaching different side groups. Two bulky groups (tertiary-butyl), indicated by a prime, prevented dimerization of neighbouring perylene chromophores when attached to the surface. Linkage to the semiconductor was achieved by different anchor-cum-spacer groups carbonic acid (-COOH) [4], propionic acid (-CH2-CH2-COOH) [2], phosphonic acid (-P(0)(OH)2) [4], methyl-phosphonic acid (-CH2-PO(OH)2) [2] and a -Tripod (see inset in Fig.2) [5], The preparation and sensitization of the nano-structured TiC>2 film and further experimental details have been described before [2]. 

An analog of this biotinylation reagent with a longer spacer arm also exists. Biotin-LC-hydrazide contains a 6-aminocaproic acid extension off its valeric acid group (Pierce). The increased length of this spacer (24.7 A) provides more efficient interaction potential with avidin or streptavidin probes, possibly increasing the sensitivity of assay systems. The reactions of biotin-LC-hydrazide are identical to those of biotin-hydrazide. 

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