Well-Defined Redox-Sensitive Polyethene Glycol-Paclitaxel Prodrug Conjugate for Tumor-Specific Delivery of Paclitaxel Using Octreotide for Tumor Targeting.

Abstract

A redox-sensitive prodrug, octreotide(Phe)-polyethene glycol-disulfide bond-paclitaxel [OCT(Phe)-PEG-ss-PTX], was successfully developed for targeted intracellular delivery of PTX. The formulation emphasizes long-circulation-time polymer-drug conjugates, combined targeting based on EPR and OCT-receptor mediated endocytosis, sharp redox response, and programmed drug release. The nontargeted redox-sensitive prodrug, mPEG-ss-PTX, and the targeted insensitive prodrug, OCT(Phe)-PEG-PTX, were also synthesized as controls. These polymer-PTX conjugates, structurally confirmed by 1H NMR, exhibited approximately 23,000-fold increase in water solubility over parent PTX and possessed drug contents ranging from 11% to 14%. The redox-sensitivity of the objective OCT(Phe)-PEG-ss-PTX prodrug was verified by in vitro PTX release profile in simulated reducing conditions, and the SSTRs-mediated endocytosis was demonstrated by flow cytometry and confocal laser scanning microscopy analyses. Consequently, compared with mPEG-PTX and OCT(Phe)-PEG-PTX, the OCT(Phe)-PEG-ss-PTX exhibited much stronger cyotoxicity and apoptosis-inducing ability against NCI-H446 tumor cells (SSTRs overexpression), whereas a comparable cytotoxicity of these prodrugs was obtained against WI-38 normal cells (no SSTRs expression). Finally, the in vivo studies on NCI-H466 tumor-bearing nude mice demonstrated that the OCT(Phe)-PEG-ss-PTX possessed superior tumor-targeting ability and antitumor activity over mPEG-PTX, OCT(Phe)-PEG-PTX and Taxol, as well as minimal collateral damage. This targeted redox-sensitive polymer-PTX prodrug system is promising in tumor therapy.

• Authors: Tingjie Yin, Qu Wu, Lei Wang, Lifang Yin, Jianping Zhou, Meirong Huo
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 12 Issue 8 Pg. 3020-31 (Aug 03 2015) ISSN: 1543-8392 [Electronic] United States
• PMID: 26086430 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Drug Carriers
• Micelles
• Polymers
• Prodrugs
• Polyethylene Glycols
• Paclitaxel
• Octreotide

Topics

• Animals
• Antineoplastic Agents, Phytogenic (administration & dosage, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Carriers (chemistry)
• Drug Delivery Systems
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Micelles
• Octreotide (chemistry)
• Oxidation-Reduction
• Paclitaxel (administration & dosage, chemistry, pharmacology)
• Polyethylene Glycols (chemistry)
• Polymers (chemistry)
• Prodrugs (chemistry)
• Small Cell Lung Carcinoma (drug therapy, metabolism, pathology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays