Spatial specific delivery of combinational chemotherapeutics to combat intratumoral heterogeneity

Kewei Wang; Maolin Jiang; Jielian Zhou; Yansong Dong; Ye Liu; Qingyu Zong; Puja Sandbhor; N D Pradeep Singh; Youyong Yuan

doi:10.1016/j.jconrel.2022.06.046

Spatial specific delivery of combinational chemotherapeutics to combat intratumoral heterogeneity

J Control Release. 2022 Aug:348:1004-1015. doi: 10.1016/j.jconrel.2022.06.046. Epub 2022 Jul 2.

Authors

Kewei Wang¹, Maolin Jiang¹, Jielian Zhou², Yansong Dong³, Ye Liu³, Qingyu Zong³, Puja Sandbhor⁴, N D Pradeep Singh⁵, Youyong Yuan⁶

Affiliations

¹ School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, PR China; National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, PR China.
² School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, PR China; Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou 510006, PR China.
³ School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, PR China; Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, PR China.
⁴ Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, 400076, India.
⁵ Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India.
⁶ School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, PR China; National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, PR China. Electronic address: yuanyy@scut.edu.cn.

PMID: 35779654
DOI: 10.1016/j.jconrel.2022.06.046

Abstract

Hypoxia-induced intratumoral heterogeneity poses a major challenge in tumor therapy due to the varying susceptibility to chemotherapy. Moreover, the spatial distribution patterns of hypoxic and normoxic tissues makes conventional combination therapy less effective. In this study, a tumor-acidity and bioorthogonal chemistry mediated in situ size transformable nanocarrier (NP@DOX_DBCO plus iCPPA_N3) was developed to spatially deliver two combinational chemotherapeutic drugs (doxorubicin (DOX) and PR104A) to combat hypoxia-induced intratumoral heterogeneity. DOX is highly toxic to tumor cells in normoxia state but less toxic in hypoxia state due to the hypoxia-induced chemoresistance. Meanwhile, PR104A is a hypoxia-activated prodrug has less toxic in normoxia state. Two nanocarriers, NP@DOX_DBCO and iCPPA_N3, can cross-link near the blood vessel extravasation sites through tumor acidity responsive bioorthogonal click chemistry to enhance the retention of DOX in tumor normoxia. Moreover, PR104A conjugated to the small-sized dendritic polyamidoamine (PAMAM) released under tumor acidity can penetrate deep tumor tissues for hypoxic tumor cell killing. Our study has demonstrated that this site-specific combination chemotherapy is better than the traditional combination chemotherapy. Therefore, spatial specific delivery of combinational therapeutics via in situ size transformable nanocarrier addresses the challenges of hypoxia induced intratumoral heterogeneity and provides insights into the combination therapy.

Keywords: Bioorthogonal chemistry; Combination chemotherapy; Intratumoral heterogeneity; Size transformable nanocarrier; Tumor hypoxia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Doxorubicin
Drug Therapy, Combination
Humans
Hypoxia
Nanoparticles* / therapeutic use
Neoplasms* / drug therapy
Neoplasms* / pathology
Prodrugs* / therapeutic use

Substances

Prodrugs
Doxorubicin