PMID- 14624622
OWN - NLM
STAT- MEDLINE
DCOM- 20040709
LR  - 20181130
IS  - 1043-1802 (Print)
IS  - 1043-1802 (Linking)
VI  - 14
IP  - 6
DP  - 2003 Nov-Dec
TI  - Polyacetal-doxorubicin conjugates designed for pH-dependent degradation.
PG  - 1096-106
AB  - Terpolymerization of poly(ethylene glycol) (PEG), divinyl ethers, and serinol can 
      be used to synthesize water soluble, hydrolytically labile, amino-pendent 
      polyacetals (APEGs) suitable for drug conjugation. As these polyacetals display 
      pH-dependent degradation (with faster rates of hydrolysis at acidic pH) and they 
      are not inherently hepatotropic after intravenous (iv) injection, they have 
      potential for development as biodegradable carriers to facilitate improved tumor 
      targeting of anticancer agents. The aim of this study was to synthesize a 
      polyacetal-doxorubicin (APEG-DOX) conjugate, determine its cytotoxicity in vitro 
      and evaluate its potential for improved tumor targeting in vivo compared to an 
      HPMA copolymer-DOX conjugate in clinical development. Amino-pendent polyacetals 
      were prepared, and following succinoylation (APEG-succ), the polymeric 
      intermediate conjugated to DOX via one of three methods using carbodiimide 
      mediated coupling (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in aqueous 
      solution was the most successful). The resultant APEG-DOX conjugates had a DOX 
      content of 3.0-8.5 wt %, contained <1.2% free DOX (relative to total DOX content) 
      and had a M(w) = 60000-100000 g/mol and M(w)/M(n) = 1.7-2.6. In vitro 
      cytotoxicity studies showed APEG-DOX to be 10-fold less toxic toward B16F10 cells 
      than free DOX (IC(50) = 6 microg/mL and 0.6 microg/mL respectively), but 
      confirmed the serinol-succinoyl-DOX liberated during main-chain degradation to be 
      biologically active. When administered iv to C57 black mice bearing subcutaneous 
      (sc) B16F10 melanoma, APEG-DOX of M(w) = 86000 g/mol, and 5.0 wt % DOX content 
      exhibited significantly (p < 0.05) prolonged blood half-life and enhanced tumor 
      accumulation compared to an HPMA copolymer-GFLG-DOX conjugate of M(w) = 30000 
      g/mol and 6.2 wt % DOX content. Moreover, APEG-DOX exhibited lower uptake by 
      liver and spleen. These observations suggest that APEG anticancer conjugates 
      warrant further development as novel polymer therapeutics for improved tumor 
      targeting.
FAU - Tomlinson, Ryan
AU  - Tomlinson R
AD  - Biomedical Polymers Group, Department of Pharmaceutics, The School of Pharmacy, 
      University of London, UK.
FAU - Heller, Jorge
AU  - Heller J
FAU - Brocchini, Steve
AU  - Brocchini S
FAU - Duncan, Ruth
AU  - Duncan R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Bioconjug Chem
JT  - Bioconjugate chemistry
JID - 9010319
RN  - 0 (Acetals)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Methacrylates)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - 80168379AG (Doxorubicin)
RN  - UKW89XAX2X (hydroxypropyl methacrylate)
SB  - IM
MH  - Acetals/*chemical synthesis/pharmacokinetics
MH  - Animals
MH  - Antineoplastic Agents/*chemical synthesis/pharmacokinetics
MH  - Cell Line, Tumor
MH  - Doxorubicin/administration & dosage/chemical synthesis/*pharmacokinetics
MH  - *Drug Delivery Systems
MH  - Drug Design
MH  - Hydrogen-Ion Concentration
MH  - In Vitro Techniques
MH  - Methacrylates/chemistry/pharmacokinetics
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Molecular Structure
MH  - Polyethylene Glycols/chemistry
MH  - Tissue Distribution
EDAT- 2003/11/20 05:00
MHDA- 2004/07/10 05:00
CRDT- 2003/11/20 05:00
PHST- 2003/11/20 05:00 [pubmed]
PHST- 2004/07/10 05:00 [medline]
PHST- 2003/11/20 05:00 [entrez]
AID - 10.1021/bc030028a [doi]
PST - ppublish
SO  - Bioconjug Chem. 2003 Nov-Dec;14(6):1096-106. doi: 10.1021/bc030028a.