Robust, active tumor-targeting and fast bioresponsive anticancer nanotherapeutics based on natural endogenous materials.

Abstract

The clinical success of cancer nanomedicines critically depends on availability of simple, safe and highly efficient nanocarriers. Here, we report that robust and multifunctional nanoparticles self-assembled from hyaluronic acid-g-poly(γ-benzyl-l-glutamate)-lipoic acid conjugates achieve a remarkably high loading (up to 25.8wt.%) and active targeted delivery of doxorubicin (DOX) to human breast tumor xenograft in vivo. DOX-loaded nanoparticles following auto-crosslinking (DOX-CLNPs) are highly stable with little drug leakage under physiological conditions while quickly release ca. 92% DOX in 30h under a cytoplasmic-mimicking reductive environment. The in vitro assays reveal that DOX-CLNPs possess a superior selectivity and antitumor activity to clinically used pegylated liposomal doxorubicin hydrochloride (DOX-LPs) in CD44 receptor overexpressing MCF-7 human breast cancer cells. Strikingly, DOX-CLNPs exhibit a superb tolerated dose of over 100mg DOX equiv./kg, which is more than 5 times higher than DOX-LPs, and an extraordinary breast tumor accumulation of 8.6%ID/g in mice. The in vivo therapeutic studies in MCF-7 human breast tumor-bearing nude mice show that DOX-CLNPs effectively inhibit tumor growth, improve survival rate, and significantly decrease adverse effects as compared to DOX-LPs. DOX-CLNPs based on natural endogenous materials with high drug loading, great stability and CD44-targetability are highly promising for precision cancer chemotherapy.

STATEMENT OF SIGNIFICANCE:

We demonstrate that with rational design, simple and multifunctional anticancer nanotherapeutics can be developed to achieve highly efficient and targeted cancer chemotherapy. Doxorubicin-loaded multifunctional nanoparticles based on hyaluronic acid-g-poly(γ-benzyl-l-glutamate)-lipoic acid conjugates exhibit a high drug loading, superior stability, fast bioresponsivity, high tolerability, and obvious selectivity toward CD44-overexpressing tumors in vivo. These nanotherapeutics achieve effective tumor suppression, drastically improved survival rate and reduced side effects as compared to clinically used pegylated liposomal doxorubicin in MCF-7 human breast tumor-bearing nude mice. Unlike previously reported multifunctional nanomedicines, the present nanotherapeutics primarily based on natural endogenous materials are simple and straightforward to fabricate, which makes them potentially interesting for clinical translation.

• Authors: Bingfeng Sun, Chao Deng, Fenghua Meng, Jian Zhang, Zhiyuan Zhong
• Journal: Acta biomaterialia (Acta Biomater) Vol. 45 Pg. 223-233 (11 2016) ISSN: 1878-7568 [Electronic] England
• PMID: 27576338 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Biocompatible Materials
• Cross-Linking Reagents
• Peptides
• liposomal doxorubicin
• poly-gamma-benzyl-L-glutamate
• Polyglutamic Acid
• Polyethylene Glycols
• Thioctic Acid
• Doxorubicin
• Hyaluronic Acid

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Biocompatible Materials (chemistry)
• Breast Neoplasms (drug therapy, pathology)
• Cross-Linking Reagents (chemistry)
• Doxorubicin (analogs & derivatives, pharmacokinetics, pharmacology, therapeutic use)
• Drug Liberation
• Female
• Humans
• Hyaluronic Acid (chemistry)
• MCF-7 Cells
• Mice, Nude
• Nanoparticles (chemistry)
• Peptides (chemical synthesis)
• Polyethylene Glycols (pharmacokinetics, pharmacology, therapeutic use)
• Polyglutamic Acid (analogs & derivatives, chemical synthesis, chemistry)
• Proton Magnetic Resonance Spectroscopy
• Thioctic Acid (chemical synthesis, chemistry)
• Tissue Distribution (drug effects)
• Xenograft Model Antitumor Assays