Reactive Oxygen Species (ROS)-Responsive Polymersomes with Site-Specific Chemotherapeutic Delivery into Tumors via Spacer Design Chemistry

Author(s):Show less -

Jager, Eliezer ^[1] ; Sincari, Vladimir ^[1] ; Albuquerque, Lindomar J. C. ^[2] ; Jager, Alessandro ^[1] ; Humajova, Jana ^[3] ; Kucka, Jan ^[1] ; Pankrac, Jan ^[4] ; Paral, Petr ^[4] ; Heizer, Tomas ^[4] ; Janouskova, Olga ^[1] ; Konefal, Rafal ^[1] ; Pavlova, Ewa ^[1] ; Sedlacek, Ondrej ^[1] ; Giacomelli, Fernando C. ^[2] ; Pouckova, Pavla ^[3] ; Sefc, Ludek ^[4] ; Stepanek, Petr ^[1] ; Hruby, Martin ^[1]

Affiliation

^[1] Inst Macromol Chem, CR-16206 Prague - Czech Republic

^[2] Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210580 Santo Andre, SP - Brazil

^[3] Charles Univ Prague, First Fac Med, Inst Biophys & Informat, Prague 12000 - Czech Republic

^[4] Charles Univ Prague, Fac Med 1, CAPI, Prague 12000 - Czech Republic

• Document type: Journal article
• Source: Biomacromolecules; v. 21, n. 4, p. 1437-1449, APR 2020.
• Web of Science Citations: 0

Abstract

The lack of cellular and tissue specificities in conventional chemotherapies along with the generation of a complex tumor microenvironment (TME) limits the dosage of active agents that reaches tumor sites, thereby resulting in ineffective responses and side effects. Therefore, the development of selective TMEresponsive nanomedicines is of due relevance toward successful chemotherapies, albeit challenging. In this framework, we have synthesized novel, ready-to-use ROSresponsive amphiphilic block copolymers (BCs) with two different spacer chemistry designs to connect a hydrophobic boronic ester-based ROS sensor to the polymer backbone. Hydrodynamic flow focusing nanoprecipitation microfluidics (MF) was used in the preparation of well-defined ROS-responsive PSs; these were further characterized by a combination of techniques {[}H-1 NMR, dynamic light scattering (DLS), static light scattering (SLS), transmission electron microscopy (TEM), and cryogenic TEM (cryo-TEM)]. The reaction with hydrogen peroxide releases an amphiphilic phenol or a hydrophilic carboxylic acid, which affects polymersome (PS) stability and cargo release. Therefore, the importance of the spacer chemistry in BC deprotection and PS stability and cargo release is herein highlighted. We have also evaluated the impact of spacer chemistry on the PS-specific release of the chemotherapeutic drug doxorubicin (DOX) into tumors in vitro and in vivo. We demonstrate that by spacer chemistry design one can enhance the efficacy of DOX treatments (decrease in tumor growth and prolonged animal survival) in mice bearing EL4 T cell lymphoma. Side effects (weight loss and cardiotoxicity) were also reduced compared to free DOX administration, highlighting the potential of the well-defined ROS-responsive PSs as TME-selective nanomedicines. The PSs could also find applications in other environments with high ROS levels, such as chronic inflammations, aging, diabetes, cardiovascular diseases, and obesity. (AU)

• FAPESP's process: 17/00459-4 - Biophysicochemical interactions at the nanobiointerface: the effect of surface features and protein corona on the cellular uptake of polymeric assemblies
• Grantee: Fernando Carlos Giacomelli
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/11261-0 - Synthesis of PHPMA-b-PDPA, PEO-b-PDPA and RGD-PHPMA-b-PDPA conjugates with further engineering of pH-responsive polymersomes towards the encapsulation and delivery of hydrophilic biomacromolecules
• Grantee: Lindomar Jose Calumby Albuquerque
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate