Two step mechanisms of tumor selective delivery of N-(2-hydroxypropyl)methacrylamide copolymer conjugated with pirarubicin via an acid-cleavable linkage
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24269967
DOI
10.1016/j.jconrel.2013.11.011
PII: S0168-3659(13)00900-0
Knihovny.cz E-resources
- Keywords
- Acid-cleavable linkage, EPR effect, HPMA polymer conjugate, Hydrazone, Pirarubicin (THP), Tumor selectivity,
- MeSH
- Acrylamides administration & dosage chemistry pharmacokinetics MeSH
- Antineoplastic Agents administration & dosage chemistry pharmacokinetics MeSH
- Doxorubicin administration & dosage analogs & derivatives chemistry pharmacokinetics MeSH
- HeLa Cells MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Neoplasms drug therapy metabolism pathology MeSH
- Drug Carriers administration & dosage chemistry pharmacokinetics MeSH
- Polymers administration & dosage chemistry pharmacokinetics MeSH
- Tissue Distribution MeSH
- Tumor Burden drug effects MeSH
- Cell Survival drug effects MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Acrylamides MeSH
- Antineoplastic Agents MeSH
- Doxorubicin MeSH
- N-(2-hydroxypropyl)methacrylamide MeSH Browser
- Drug Carriers MeSH
- pirarubicin MeSH Browser
- Polymers MeSH
N-(2-Hydroxypropyl)methacrylamide copolymer containing hydrazide groups (PHPMA) conjugated with pirarubicin (THP) via a hydrazone bond (PHPMA-hyd-THP) is a drug conjugate that releases THP in the acidic milieu of a tumor. PHPMA-hyd-THP has an apparent Mw of 40,000 and a hydrodynamic diameter of 8.2±1.7nm but no apparent plasma protein binding. PHPMA-hyd-THP possesses two mechanisms of selectivity toward solid tumors and has potent antitumor action. The first one is drug accumulation in tumors that depends on the enhanced permeability and retention (EPR) effect, which results in a 4-20 times higher concentration of drug in the tumor than in normal tissues such as the heart, lung, and intestine. This accumulation in tumor tissue is in great contrast to that of conventional low-Mw THP. The second one is pH-dependent release of drug from PHPMA-hyd-THP: this conjugate released free THP more efficiently at a lower pH, which exists in tumors, and exerts cytotoxic activity. Free THP is known for its much faster uptake into tumor cells compared with doxorubicin. Thus, in our in vitro study, PHPMA-hyd-THP showed a higher cytotoxicity at the lower pH of tumor tissue than at the neutral pH of normal tissue. Furthermore, much more THP was liberated from the conjugate in acidic tumor tissue than in normal tissue. The EPR effect-dependent accumulation of PHPMA-hyd-THP and tumor-selective THP release in the tumor tissues led to highly tumor-selective drug accumulation, which continued for more than 72h, whereas the lowest free drug concentration was detected in normal tissues at 24h and no longer at a later time. In conclusion, we determined in our study here that the acid-cleavable PHPMA-hyd-THP conjugate had an excellent antitumor effect without appreciable adverse effects.
J Control Release. 2014 May 28;182:97-8 PubMed
References provided by Crossref.org
HPMA Copolymer-Based Nanomedicines in Controlled Drug Delivery
Structure-to-Efficacy Relationship of HPMA-Based Nanomedicines: The Tumor Spheroid Penetration Study
