Use of Block Copolymers of Poly(Ortho Esters) and Poly (Ethylene Glycol) Micellar Carriers as Potential Tumour Targeting Systems

Abstract

Amphiphilic AB and ABA block copolymers have been prepared from poly (ortho esters) and poly (ethylene glycol). Such block copolymers readily form micellar dispersions in water, or buffers. The CMC is in the range of 3 x 10(-4)-5 x 10(-4) g/l which is a value low enough to assure retention of micelle integrity upon intravenous injection. The size, as determined by dynamic light scattering was in the 40-70 nm range. The micelles can be stored in lyophilized form for at lest 8 months and easily reconstituted to the original properties. The micelles are stable in PBS at pH 7.4 and 37 degrees C for 3 days and in a citrate buffer at pH 5.5 and 37 degrees C for 2 h. Stability in the presence of bovine serum albumin depends on the structure of the block copolymer and especially the length of the POE block.

Comparative Investigations on In Vitro Serum Stability of Polymeric Micelle Formulations

“…Although PEG-PVPy [2-b-10] had a higher hydrophobic/hydrophilic ratio than PEG-PVPy [5-b-20], the latter was more stable, indicating that the size of the hydrophobic part is more decisive in determining the serum stability than the size of the PEG part. The same conclusion was drawn by Toncheva et al when investigating the stability of PEG-polyorthoester ABA triblock polymers against bovine serum albumin (36).…”

Amphiphilic Block Copolymers Bearing Ortho Ester Side‐Chains: pH‐Dependent Hydrolysis and Self‐Assembly in Water

“…[57] Third, mildly acidic environments found in the endosome of cells and inflammatory tissues may catalyze the hydrolysis of the ortho ester side-chains of PEG-b-PMYM. Unlike many acidlabile block copolymer micelles, [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] the PEG-b-PMYM nanoparticles do not dissolve after hydrolysis but persist as large particles several times their initial size, which potentially allows more efficient retention at the target tissue and more sustained release of drugs. Finally, the ability to chemically tune the pH-response and assembly/ disassembly of the polymer chains and nanostructures is a potentially attractive feature of the PEG-b-PMYM system, and it may inspire better, more sophisticated designs of drug carriers.…”

“…[30][31][32][33][34][35][36][37] Activation of drug release relies on acid-catalyzed cleavage of the linker, which is dictated by the intrinsic chemical reactivity of bonds and is often not amenable to fine-tuning. The third strategy is to create polymers with acid-degradable main-chains, for example, in poly(ethylene glycol) (PEG)-based diblock copolymers where the hydrophobic block is polyacetal [38] or poly(b-amino esters). [39] In an acidic environment, the hydrophobic blocks undergo rapid main-chain scission, thereby releasing hydrophobic drugs encapsulated in the nanoparticles.…”

Design, Synthesis, and Characterization of pH-Sensitive PEG−PE Conjugates for Stimuli-Sensitive Pharmaceutical Nanocarriers: The Effect of Substitutes at the Hydrazone Linkage on the pH Stability of PEG−PE Conjugates

“…Different approaches have been employed to develop pH-responsive carriers, one being incorporation of acidsensitive linkages between drug-ligand or into the molecules of the carrier-forming components. These include cis-aconityls (18,19), electron-rich trityls (20), polyketals (21), acetals (22,23), vinyl ethers (24,25), hydrazones (26)(27)(28), poly(ortho-esters) (29), and thiopropionates (30). Such constructs may turn out to be useful for the site-specific delivery of drugs at the tumor sites (12), infarcts (31), inflammation zones (32) or cell cytoplasm or endosomes (33), since at these "acidic" sites, pH drops from the normal physiologic value of pH 7.4 to pH 6.0 and below.…”