pH-Sensitive morphological transitions in polymeric tadpole assemblies for programmed tumor therapy

Abstract

Ultrafine single-chain tadpole polymers (SCTPs), containing an intrachain cross linked globule and a pH-sensitive linear polymer chain, have been synthesized. Self-assembly of these polymers depends on the linear block length and the pH, at which the polymer is assembled. Although the SCTPs themselves exhibit a size that is consistent with a single-chain species, the self-assembled SCTPs were found to be substantially larger. Since the transition between these two structures is reversibly dependent on pH, we explored the possibility of utilizing these assemblies to achieve deep tissue penetration in tumors. Our results indicate that there is indeed a pH-dependent deep tissue penetration in ex vivo tumor multicellular spheroids. Moreover, the multi-tadpole assemblies (MTAs) can stably encapsulate hydrophobic molecules, which has been used to encapsulate paclitaxel (PTX). These PTX/MTAs show excellent therapeutic efficacy and biosafety in 4T1 xeno graft mouse models. The innovative multi-compartment aggregates are able to fulfill structure-related function transitions with the variation of microenvironment, which has potential to extremely enrich the design of sophisticated biological agents.

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

“…Then, the time‐dependent decrease of scattering intensity was measured, which reveals that the size transition of IR780‐PDMs at acidic pH can be accomplished within 10 min (Figure S6, Supporting Information). Compared with our previous work, this relative long dissociation time might be attributed to the strong π–π stacking effect among the polymeric chains. Meanwhile, the dissociation of IR780‐PDMs into small particles around 10 nm can be observed in Figure S7 (Supporting Information).…”

Multi-Smart and Scalable Bioligands-Free Nanomedical Platform for Intratumorally Targeted Tambjamine Delivery, a Difficult to Administrate Highly Cytotoxic Drug

“…This has led to the exploration of different nanosized systems with pH-responsive properties for cancer treatment [ 13 ]. One example is the development of nanoparticles with a large structure to avoid blood clearance that shrink once pH decreases in tumor, enhancing cell penetration [ 14 ]. Another study describes the synthesis of nanosystems that are chemically stable under physiological conditions but release the encapsulated drug when pH conditions become acidic, showing an improved tolerability in blood [ 15 ].…”

Towards principled design of cancer nanomedicine to accelerate clinical translation

“…For example, at pH 7.4, shape-changing single-chain polymers become deprotonated and hydrophobic, causing them to self-aggregate into large (68.7 ​± ​2.8 ​nm) spherical “multi-tadpole assemblies” (MTAs). When exposed to decreased pH (6.9), they disassemble into 9.6 ​nm rod-shaped nanoparticles, which then penetrate deeper into tissue [ 179 ]. Other studies have shown an improvement in therapeutic response through enhanced biocompatibility, biodistribution, and the induction of a potent antitumor immune response by transforming spherical nanoparticles into nanofibers in response to light and ROS stimuli [ 180 , 181 ].…”