CD44-Targeted Multifunctional Nanomedicines Based on a Single-Component Hyaluronic Acid Conjugate with All-Natural Precursors: Construction and Treatment of Metastatic Breast Tumors in Vivo.

Abstract

Metastasis is responsible for >90% of the deaths of breast cancer patients in the clinic. Here, we report on cross-linked multifunctional hyaluronic acid nanoparticles carrying docetaxel (DTX-CMHN) for enhanced suppression of highly metastatic 4T1 breast tumors in vivo. DTX-CMHN was formed from a single and all-natural hyaluronic acid-g-polytyrosine-lipoic acid conjugate (HA-g-PTyr-LA; HA, 20 kDa; PTyr, 2.2 kDa), and the size of DTX-CMHN increased from 69 to 78 to 96 nm as the increasing degree of substitution (DS) of PTyr increased from 4 to 11 to 15, respectively. Robust encapsulation of DTX was obtained when DS ≥ 11. DTX-CMHN while steady in a nonreducing environment was destabilized under 10 mM glutathione releasing ∼90% of the DTX within 24 h. It is noteworthy that DTX-CMHN exhibited better antitumor, antimigration, and anti-invasion activity in CD44-overexpressed 4T1-Luc breast cancer cells than free DTX. Interestingly, DTX-CMHN displayed a long elimination half-life of 5.75 h, in contrast to half-lives of 2.11 and 0.75 h for its non-cross-linked counterpart (DTX-MHN) and free DTX, respectively. In vivo therapeutic studies showed significantly better inhibition of primary 4T1-Luc tumor growth and lung metastasis and lower toxicity of DTX-CMHN compared with that of free DTX. These multifunctional nanoformulations based on a single and all-natural hyaluronic acid conjugate emerge as a potential nanoplatform for targeted treatment of CD44-positive metastatic tumors.

• Authors: Huimin Fang, Xiaofei Zhao, Xiaolei Gu, Huanli Sun, Ru Cheng, Zhiyuan Zhong, Chao Deng
• Journal: Biomacromolecules (Biomacromolecules) Vol. 21 Issue 1 Pg. 104-113 (01 13 2020) ISSN: 1526-4602 [Electronic] United States
• PMID: 31532629 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• CD44 protein, human
• Drug Carriers
• Hyaluronan Receptors
• Docetaxel
• Tyrosine
• Thioctic Acid
• Hyaluronic Acid

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Breast Neoplasms (drug therapy, pathology)
• Docetaxel (administration & dosage, pharmacokinetics)
• Drug Carriers (administration & dosage, chemistry, pharmacokinetics)
• Drug Delivery Systems (methods)
• Female
• Humans
• Hyaluronan Receptors
• Hyaluronic Acid
• Lung Neoplasms (drug therapy, pathology, secondary)
• Mice
• Molecular Targeted Therapy (methods)
• Nanomedicine (methods)
• Nanoparticles (administration & dosage, chemistry)
• Thioctic Acid (chemistry)
• Tissue Distribution
• Tyrosine (chemistry)
• Xenograft Model Antitumor Assays