RESUMO
Tailor-made copolymers are designed based on a peptide-poly(ethylene glycol) (QFFLFFQ-PEG) conjugate as a blueprint, to solubilize the photosensitizer meta-tetra(hydroxyphenyl)chlorin (m-THPC). The relevant functionalities of the parent peptide-PEG are mimicked by employing monomer pairs that copolymerize in a strictly alternating manner. While styrene (S) or 4-vinylbenzyl-phthalimide (VBP) provide aromatic moieties like Phe, the aliphatic isobutyl side chain of Leu4 is mimicked by maleic anhydride (MA) that reacts after polymerization with isobutylamine to give the isobutylamide-carboxyl functional unit (iBuMA). A set of copolymer-PEG solubilizers is synthesized by controlled radical polymerization, systematically altering the length of the functional segment (DPn = 2, 4, 6) and the side chain functionalization (iBuMA, iPrMA, MeMA). The m-THPC hosting and release properties of P[S-alt-iBuMA]6-PEG reached higher payload capacities and more favored release rates than the parent peptide-PEG conjugate. Interestingly, P[S-alt-RMA]n-PEG mimics the sensitivity of the peptide-PEG solubilizer well, where the exchange of Leu4 residue by Val and Ala significantly reduces the drug loading by 92%. A similar trend is found with P[S-alt-RMA]n-PEG as the exchange of iBu â iPr â Me reduces the payload capacity up to 78%.
Assuntos
Fármacos Fotossensibilizantes , Polietilenoglicóis , Composição de Medicamentos , Micelas , PolímerosRESUMO
Functional precision polymers based on monodisperse oligo(N-substituted acrylamide)s and oligo(2-substituted-α-hydroxy acid)s have been synthesized. The discrete sequences originate from a direct translation of side-chain functionality sequences of a peptide with well-studied properties. The peptide was previously selected to solubilize the photosensitizer meta-tetra(hydroxyphenyl)chlorin. The resulting peptidomimetic formulation additives preserve the drug solubilization and release characteristics of the parent peptide. In some cases, superior properties are obtained, reaching up to 40 % higher payloads and 27-times faster initial drug release.
RESUMO
Functional sequences of monodisperse, sequence-defined oligo(amide-urethane)s are designed based on a peptide sequence as blueprint. The translation of a discrete side-chain functionality sequence from a known peptide-based solubilizer of the photosensitizer meta-tetra(hydroxyphenyl)-chlorin, into a non-peptidic precision polymer backbone is demonstrated. The resulting peptidomimetic precision polymers retain the functions of the parent peptide sequence, showing analogues sensitivity toward single monomer mutations/exchanges and even exceeding the parent peptide equivalent by reaching up to 69% higher payload capacities and more favored release kinetics.
Assuntos
Peptídeos/química , Fármacos Fotossensibilizantes/química , Polietilenoglicóis/química , Porfirinas/químicaRESUMO
Using peptide sequences for the design of functional peptoids is demonstrated for a peptide-based formulation additive that was specifically tailored to solubilize the photosensitizer meta-tetra(hydroxyphenyl)-chlorin. A set of peptoid-block-poly(ethylene glycol) solubilizers with systematic sequence variations are synthesized to reveal contributions of side-chain sequence and backbone functionalities on drug hosting and release properties. The drug payload sensitively depends on the side-chain patterns, and the best performing peptoid sequence reaches 3-times higher capacity than the corresponding peptide. The peptoid backbone not only acts as a neutral scaffold but also impacts the drug release kinetics compared to the analogues peptide, by reducing the capability to assist drug transfer to blood plasma protein models.