A cationic polymeric prodrug with chemotherapeutic self-sensibilization co-delivering MMP-9 shRNA plasmid for a combined therapy to nasopharyngeal carcinoma

Tao Liu; Xidong Wu; Shaohua Chen; Peina Wu; Hong Han; Hongbin Zhang; Junzheng Li; Guanxue Li; Siyi Zhang

doi:10.1080/10717544.2019.1698674

A cationic polymeric prodrug with chemotherapeutic self-sensibilization co-delivering MMP-9 shRNA plasmid for a combined therapy to nasopharyngeal carcinoma

Drug Deliv. 2019 Dec;26(1):1280-1291. doi: 10.1080/10717544.2019.1698674.

Authors

Tao Liu¹, Xidong Wu², Shaohua Chen¹, Peina Wu¹, Hong Han¹, Hongbin Zhang¹, Junzheng Li³, Guanxue Li⁴, Siyi Zhang¹

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
² Department of Drug Safety Evaluation, Jiangxi Testing Center of Medical Device, Nanchang, China.
³ Department of Otolaryngology-Head and Neck Surgery, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, China.
⁴ Department of Pediatric Center, Zhujiang Hospital of Southern Medical University, Guangzhou, China.

Abstract

To obtain a high-efficiency drug and gene co-delivery system to HNE-1 tumor therapy, a polymeric prodrug (PAAs-MTX) with chemotherapeutic sensibilization was synthesized consisting of a GSH-response hyperbranched poly(amido amine) (PAAs) and an antitumor drug of methotrexate (MTX). Then, the targeting molecule to HNE-1 cells, transferrin (Tf), was conjugated to form the Tf-PAAs-MTX. This polymeric prodrug could deliver MMP-9 shRNA plasmid (pMMP-9) again to form the drug and gene co-delivery system of Tf-PAAs-MTX/pMMP-9. The co-delivery system showed the effective drug and gene delivery ability with high cytotoxicity and gene transfection efficiency to HNE-1 cells. Besides that, Tf-PAAs-MTX also showed the chemotherapeutic sensibilization effect, the formulation containing PAAs segments showed much higher cytotoxicity than that of free MTX. Benefiting from the sensibilization effect and MTX/pMMP-9 co-delivery strategy, this Tf-PAAs-MTX/pMMP-9 co-delivery system exhibited the significantly improved therapeutic efficacy to HNE-1 tumor in a combined manner which was confirmed by in vitro and in vivo assays. Moreover, its biocompatibility, especially the blood compatibility was analyzed. This polymeric prodrug provided an easily delivery system combining the drug/gene co-delivery, chemotherapeutic sensibilization and targeting into one single platform, which showed a promising application in nasopharyngeal carcinoma therapy.

Keywords: Chemotherapeutic sensibilization; drug and gene co-delivery; nasopharyngeal carcinoma; polymeric prodrug.

MeSH terms

3T3 Cells
Animals
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Apoptosis / genetics
Cell Line, Tumor
Combined Modality Therapy
Drug Delivery Systems / methods*
Gene Transfer Techniques*
Matrix Metalloproteinase 9 / administration & dosage*
Matrix Metalloproteinase 9 / genetics
Methotrexate / administration & dosage*
Methotrexate / therapeutic use
Mice
Mice, Nude
Nasopharyngeal Carcinoma / therapy*
Plasmids / administration & dosage*
Plasmids / genetics
Polyamines / chemistry*
Prodrugs / administration & dosage*
Prodrugs / therapeutic use
RNA, Small Interfering / administration & dosage*
RNA, Small Interfering / genetics
Transfection
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Poly(amidoamine)
Polyamines
Prodrugs
RNA, Small Interfering
Matrix Metalloproteinase 9
Methotrexate

Grants and funding

This work was financially supported by the National Natural Science Foundation of China [81573000], the Natural Science Foundation of Guangdong Province, China [2019A1515011678], the talent introduction fund of Guangdong Provincial People’s Hospital [Y012018142] and the matching scientific research fund for Guangdong Provincial outstanding young medical talent by Guangdong Provincial People’s Hospital [KJ012019454].