Zwitterionic Polysulfamide Drug Nanogels with Microwave Augmented Tumor Accumulation and On‐Demand Drug Release for Enhanced Cancer Therapy

Abstract

Zwitterionic polymers demonstrate as a class of antifouling materials with long blood circulation in living subjects. Despite extensive research on their antifouling abilities, the responsive zwitterionic polymers that can change their properties by mild outside signals are poorly explored. Herein, a sulfamide‐based zwitterionic monomer is developed and used to synthesize a series of polysulfamide‐based (poly (2‐((2‐(methacryloyloxy)ethyl) dimethylammonio)acetyl) (phenylsulfonyl) amide (PMEDAPA)) nanogels as drug carriers for effective cancer therapy. PMEDAPA nanogels are proved to exhibit prolonged blood circulation without inducing the accelerated blood clearance phenomenon. Intriguingly, PMEDAPA nanogels can sensitively respond to hyperthermia by adjusting the crosslinker degree. After modified with transferrin (Tf), the nanogels (PMEDAPA‐Tf) achieve shielded tumor targeting at normothermia, while exhibiting recovered tumor targeting at hyperthermia, leading to enhanced tumor accumulation. Meanwhile, PMEDAPA‐Tf nanogels show superior penetration ability in 3D tumor spheroids and faster drug release at hyperthermia compared with that at normothermia. In combination with mild microwave heating (≈41 °C), the drug‐loaded PMEDAPA‐Tf nanogels show a pronounced tumor inhibition effect in a humanized orthotropic liver cancer model. Therefore, the study provides a novel hyperthermia‐responsive zwitterionic nanogel that can achieve augmented tumor accumulation and on‐demand drug release assisted with clinically used microwave heating for cancer therapy.

Zwitterionic Nanogels and Microgels: An Overview on Their Synthesis and Applications

“…The higher the cross-linker molar ratio used, the higher is the VPTT of the nanogels due to their more compact network structures (see Figure 2d,e). [113] Moreover, the PMEDAPA nanogels showed excellent biocompatibility and b) their UV-vis cloud points at different microgel concentrations. Reproduced with permission.…”

“…Change in UCST-type VPTT of PMEDAPA nanogels d) PMEDAPA-54 and e) PMEDAPA-64; where PMEDAPA-54 and 64 stand for PMEDAPA nanogels prepared with 54 and 64 molar ratios of cross-linker, respectively. Reproduced with permission [113]. Copyright 2017, John Wiley & Sons.…”

Applications of Surface Modification Technologies in Nanomedicine for Deep Tumor Penetration

“…In another study, transferrin was used to enhance the tumor penetration of polysulfamide‐based (poly(2‐((2‐(methacryloyloxy)ethyl) dimethylammonio)acetyl) (phenylsulfonyl) amide) nanogels. [ 91 ] These nanogels showed a favorable penetration ability in 3D tumor spheroids.…”

Recent Advances in Crosslinked Nanogel for Multimodal Imaging and Cancer Therapy

“…In vivo studies indicated that POSS-PEG-Ce6 NPs can effectively accumulate into tumor of mice, and showed good PDT efficacy against tumor. Lu et al designed a microwave-responsive nanogel for on-demand drug delivery and enhanced cancer therapy [ 64 ]. Such nanogels were synthesized by crosslinking zwitterionic monomer (2-((2-(methacryloyloxy)ethyl) dimethylammonio)acetyl) (phenylsulfonyl) amide (MEDAPA) with ethyleneglycol dimethacrylate (EGDMA) and bis(acryloyl)cystamine (BAC).…”