Oral delivery of shRNA based on amino acid modified chitosan for improved antitumor efficacy.

Abstract

In this investigation, chitosan-histidine-cysteine (CHC) was engineered for oral delivery of Survivin short hairpin RNA (shRNA)-expressing plasmid DNA (shSur-pDNA) to promote hepatoma regression through integrating the advantages of histidine and cysteine to conquer serial cellular and systemic barriers. CHC could effectively encapsulate shSur-pDNA to form compact nanocomplexes (NC) at adequate weight ratios. Sequential modification with histidine and cysteine conferred CHC NC with the beneficial attributes for shRNA delivery including improved stability, facilitated internalization, promoted endosomal escape, increased nuclear localization, and GSH-responsive release, which contributed to their superior performance in terms of apoptosis promotion, proliferation inhibition, and Survivin down-regulation of tumor cells. More importantly, in hepatoma-bearing mice, orally delivered CHC NC overweighed chitosan counterparts with respect to suppressed Survivin expression, retarded tumor growth, and prolonged surviving time, owing to their above-mentioned merits in combination with enhanced intestinal permeation. Especially, rapid intracellular release of CHC NC with lower molecular weight of 30 kDa (CHC30 NC) might be responsible for the most satisfactory antitumor efficacy with tumor inhibition ratio (TIR) of 92.5%, which rendered CHC30 NC a promising vehicle for oral delivery of shRNA. This investigation would shed light on the deliberate design of oral shRNA delivery vehicles to mediate effective antitumor efficacy.

• Authors: Hao Zheng, Cui Tang, Chunhua Yin
• Journal: Biomaterials (Biomaterials) Vol. 70 Pg. 126-37 (Nov 2015) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 26310108 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• BIRC5 protein, human
• Buffers
• Inhibitor of Apoptosis Proteins
• Polymers
• RNA, Small Interfering
• Survivin
• Histidine
• DNA
• Chitosan
• Cysteine

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Buffers
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chitosan (chemistry)
• Cysteine (chemistry)
• DNA (metabolism)
• Endocytosis (drug effects)
• Histidine (chemistry)
• Inhibitor of Apoptosis Proteins (metabolism)
• Intracellular Space (metabolism)
• Mice
• Nanoparticles (chemistry, toxicity)
• Particle Size
• Plasmids (metabolism)
• Polymers (chemistry)
• Proton Magnetic Resonance Spectroscopy
• RNA, Small Interfering (administration & dosage)
• Static Electricity
• Survivin
• Treatment Outcome