Long‐Circulating Drug‐Dye‐Based Micelles with Ultrahigh pH‐Sensitivity for Deep Tumor Penetration and Superior Chemo‐Photothermal Therapy

Abstract

Nanocarriers for chemo‐photothermal therapy suffer from insufficient retention at the tumor site and poor penetration into tumor parenchyma. A smart drug‐dye‐based micelle is designed by making the best of the structural features of small‐molecule drugs. P‐DOX is synthesized by conjugating doxorubicin (DOX) with poly(4‐formylphenyl methacrylate‐co‐2‐(diethylamino) ethyl methacrylate)‐b‐polyoligoethyleneglycol methacrylate (P(FPMA‐co‐DEA)‐b‐POEGMA) via imine linkage. Through the π–π stacking interaction, IR780, a near‐infrared fluorescence dye as well as a photothermal agent, is integrated into the micelles (IR780‐PDMs) with the P‐DOX. The IR780‐PDMs show remarkably long blood circulation (t1/2β = 22.6 h). As a result, a progressive tumor accumulation and retention are presented, which is significant to the sequential drug release. Moreover, when entering into a moderate acidic tumor microenvironment, IR780‐PDMs can dissociate into small‐size conjugates and IR780, which obviously increases the penetration depth of drugs, and then improves the lethality to deep‐seated tumor cells. Owing to the high delivery efficiency and superior chemo‐photothermal therapeutic efficacy of IR780‐PDMs, 97.6% tumor growth in the A549 tumor‐bearing mice is suppressed with a low dose of intravenous injection (DOX, 1.5 mg kg−1; IR780, 0.8 mg kg−1). This work presents a brand‐new strategy for long‐acting intensive cancer therapy.

Nanodrug Delivery Systems Modulate Tumor Vessels to Increase the Enhanced Permeability and Retention Effect

“…However, due to the existence of various barriers, they often have difficulty in reaching the core of the tumor. Therefore, nanodrugs of variable size can be used to simultaneously achieve long-time circulation, good passive targeting, and high permeability [ 178 , 179 , 180 , 181 , 182 , 183 ].…”

Direct Polymerization Approach to Synthesize Acid‐Degradable Block Copolymers Bearing Imine Pendants for Tunable pH‐Sensitivity and Enhanced Release

“…Typical approach to synthesize core-degradable ABPs involves the postpolymerization conjugation. Functional copolymer precursors bearing primary amine or aldehyde pendants are conjugated with hydrophobes, [21,22] drug molecules, [23][24][25] and hydrophilic species [26][27][28] through in situ formation of imine linkages. Although a number of elegant methods have been reported, this approach poses several limitations: lower conjugation efficiency, batch-tobatch variation, and scale-up complexity.…”

Polycarbonate-based ultra-pH sensitive nanoparticles improve therapeutic window

“…For example, extracellular pH of tumors is reported ~6.8 and early endosomal pH is at 6.5 4 . Small molecular or non-cooperative polymeric pH-sensitive systems are not efficient to respond to these subtle pH differences, which prompted successful development of various smart materials with improved pH sensitivity and response 11 – 13 .…”