Serum albumin-protamine conjugate for biocompatible platform for targeted delivery of therapeutic macromolecules.
A well-defined, one-to-one conjugate between human serum albumin (HSA) and protamine was synthesized and characterized as a biocompatible carrier for macromolecules. In circulation, the conjugate will camouflage drug molecules upon complex formation, while liberating free drug at the desired location using a triggering mechanism. The N-terminus of protamine was thiolated and conjugated with the unpaired Cysteine-34 of HSA, and was purified by ion-exchange chromatography. The molecular weight of the conjugate was 70.8 kDa, confirming one-to-one conjugation between HSA (66.6 KDa) and protamine (4200 Da). Superimposed fluorescence spectra of native HSA and HSA-protamine conjugate indicated no conformational change around the Trp-214. The conjugate had marked reduction in hemolytic and cytotoxic properties compared to protamine. When therapeutic potential was tested using tissue plasminogen activator as a model drug, HSA-protamine conjugate suppressed the enzymatic activity by 65%, which was fully recovered by a triggering agent, heparin. The construct showed binding characteristics with activated platelets upon conjugation with a targeting peptide, demonstrating flexibility to introduce suitable homing moiety on the surface. The camouflaged construct retained triggered release property in human plasma condition. Overall, the conjugate has a good potential to serve as a biocompatible platform for macromolecular drugs.
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter St, Amarillo, Texas, 79106.
Shahriar
S
Absar
Kamrun
K
Nahar
Suna
S
Choi
Fakhrul
F
Ahsan
Victor C
VC
Yang
Young M
YM
Kwon
D001672:Biocompatible Materials / Q000737:chemistry*; D002852:Chromatography, Ion Exchange; D016503:Drug Delivery Systems; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D046911:Macromolecular Substances / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D010455:Peptides / Q000378:metabolism; D015539:Platelet Activation; D011479:Protamines / Q000737:chemistry*; D055550:Protein Stability; D012709:Serum Albumin / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013438:Sulfhydryl Compounds / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D001672:Biocompatible Materials; D046911:Macromolecular Substances; D010455:Peptides; D011479:Protamines; D012709:Serum Albumin; D013438:Sulfhydryl Compounds; D006493:Heparin; D010959:Tissue Plasminogen Activator
albumin as a carrier; albumin-based delivery; localized thrombolysis; prodrug strategy for macromolecules