The permeability and responsiveness of polymer membranes are absolutely relevant in the design of polymersomes for cargo delivery. Accordingly, we herein correlate the structural features, permeability, and responsiveness of doxorubicin-loaded (DOX-loaded) nonresponsive and stimuli-responsive polymersomes with their in vitro and in vivo antitumor performance. Polymer vesicles were produced using amphiphilic block copolymers containing a hydrophilic poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) segment linked to poly[N-(4-isopropylphenylacetamide)ethyl methacrylate] (PPPhA, nonresponsive block), poly[4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)benzyl methacrylate] [PbAPE, reactive oxygen species (ROS)-responsive block], or poly[2-(diisopropylamino)ethyl methacrylate] (PDPA, pH-responsive block). The PDPA-based polymersomes demonstrated outstanding biological performance with antitumor activity notably enhanced compared to their counterparts. We attribute this behavior to a fast-triggered DOX release in acidic tumor environments as induced by pH-responsive polymersome disassembly at pH < 6.8. Possibly, an insufficient ROS concentration in the selected tumor model attenuates the rate of ROS-responsive vesicle degradation, whereas the nonresponsive nature of the PPPhA block remarkably impacts the performance of such potential nanomedicines.

• MeSH
• Acrylamides chemistry   pharmacology   MeSH
• Doxorubicin * pharmacology   chemistry   MeSH
• Hydrogen-Ion Concentration MeSH
• Humans MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Drug Carriers chemistry   MeSH
• Cell Membrane Permeability drug effects   MeSH
• Polymers chemistry   pharmacology   MeSH
• Antibiotics, Antineoplastic pharmacology   chemistry   MeSH
• Antineoplastic Agents pharmacology   chemistry   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Acrylamides MeSH
• Doxorubicin * MeSH
• Drug Carriers MeSH
• Polymers MeSH
• Antibiotics, Antineoplastic MeSH
• Antineoplastic Agents MeSH
• Reactive Oxygen Species MeSH

The antitumor immunity can be enhanced through the synchronized codelivery of antigens and immunostimulatory adjuvants to antigen-presenting cells, particularly dendritic cells (DCs), using nanovaccines (NVs). To study the influence of intracellular vaccine cargo release kinetics on the T cell activating capacities of DCs, we compared stimuli-responsive to nonresponsive polymersome NVs. To do so, we employed "AND gate" multiresponsive (MR) amphiphilic block copolymers that decompose only in response to the combination of chemical cues present in the environment of the intracellular compartments in antigen cross-presenting DCs: low pH and high reactive oxygen species (ROS) levels. After being unmasked by ROS, pH-responsive side chains are exposed and can undergo a charge shift within a relevant pH window of the intracellular compartments in antigen cross-presenting DCs. NVs containing the model antigen Ovalbumin (OVA) and the iNKT cell activating adjuvant α-Galactosylceramide (α-Galcer) were fabricated using microfluidics self-assembly. The MR NVs outperformed the nonresponsive NV in vitro, inducing enhanced classical- and cross-presentation of the OVA by DCs, effectively activating CD8+, CD4+ T cells, and iNKT cells. Interestingly, in vivo, the nonresponsive NVs outperformed the responsive vaccines. These differences in polymersome vaccine performance are likely linked to the kinetics of cargo release, highlighting the crucial chemical requirements for successful cancer nanovaccines.

• MeSH
• Adjuvants, Immunologic pharmacology   MeSH
• Antigens chemistry   MeSH
• CD8-Positive T-Lymphocytes MeSH
• Dendritic Cells MeSH
• Hydrogen-Ion Concentration MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Nanovaccines * MeSH
• Ovalbumin MeSH
• Reactive Oxygen Species MeSH
• Vaccines * chemistry   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adjuvants, Immunologic MeSH
• Antigens MeSH
• Nanovaccines * MeSH
• Ovalbumin MeSH
• Reactive Oxygen Species MeSH
• Vaccines * MeSH