Hydrogen-Bonded Polymer Nanomedicine with AIE Characteristic for Intelligent Cancer Therapy.

One of the major goals of biomedical science is to pioneer advanced strategies toward precise and smart medicine. Hydrogen-bonding (H-bonding) assembly incorporated with an aggregation-induced emission (AIE) capability can serve as a powerful tool for developing supramolecular nanomedicine with clear tumor imaging and smart therapeutic performance. We here report a H-bonded polymeric nanoformulation with an AIE characteristic toward smart antitumor therapy. To do so, we first design a structurally novel tetraphenylethylene (TPE)-based H-bonding theranostic prodrug, TPE-(FUA)4, characterized by four chemotherapeutic fluorouracil-1-acetic acid (FUA) moieties arched to the TPE core. A six-arm star-shaped amphiphilic polymer vehicle, P(DAP-co-OEGEA)6, is prepared, bearing hydrophilic and biocompatible POEGEA (poly(oligo (ethylene glycol) ethyl acrylate) segments, along with a hydrophobic and H-bonding PDAP (poly(diaminopyridine acrylamide)) segment. Thanks to the establishment of the DAP/FUA H-bonding association, incorporating the TPE-(FUA)4 prodrug to the P(DAP-co-OEGEA)6 vehicle can yield H-bond cross-linked nanoparticles with interpenetrating networks. For the first time, AIE luminogens are interwoven into a six-arm star-shaped polymer via an intrinsic H-bonding array of the chemotherapeutic agent FUA, thus imposing an effective restriction of TPE molecular rotations. Concomitantly, encapsulated photothermal agent (IR780) via a hydrophobic interaction facilitates the formation of nanoassemblies, TPE-(FUA)4/IR780@P(DAP-co-OEGEA)6, featuring synergistic cancer chemo/photothermal therapy (CT/PTT). Our study can contribute a practical solution to fulfill biomedical requirements with a conductive advance in precision nanomedicine.

Starvation-assisted and photothermal-thriving combined chemo/chemodynamic cancer therapy with PT/MR bimodal imaging.

Chemodynamic therapy (CDT) reflects a novel reactive oxygen species (ROS)-related cancer therapeutic approach. However, CDT monotherapy is often limited by weak efficacy and insufficient endogenous H2O2. Herein, a multifunctional combined bioreactor (MnFe-LDH/MTX@GOx@Ta, MMGT) relying on MnFe-layered double hydroxide (MnFe-LDH) loaded with methotrexate (MTX) and coated with glucose oxidase (GOx)/tannin acid (Ta) is established for applications in H2O2 self-supply and photothermal enhanced chemo/chemodynamic combined therapy along with photothermal (PT) /magnetic resonance (MR) dual-modality imaging ability for cancer treatment. Once internalized into tumor cells, MMGT achieves starvation therapy by catalyzing the oxidation of glucose with GOx, accompanied by the regeneration of H2O2, enabling a Fenton-like reaction to accomplish GOx catalytic amplified CDT. Moreover, MMGT manifests significant tumor-killing ability through improved CDT performance with outstanding photothermal conversion efficiency (η = 52.2%) under 808 nm laser irradiation. In addition, the release of Mn2+ from MnFe-LDH in a solid tumor can significantly enhance T1-contrast MR imaging signals. Combined with MnFe-LDH-induced PT imaging under 808 nm laser irradiation, a dual-modality imaging directed theranostic nanoplatform has been developed. The present study provides a new strategy to design H2O2 self-supply and ROS evolving NIR light-absorption theranostic nanoagent for highly efficient and combined chemo/chemodynamic cancer treatment.

Core-Coordinated Elliptic Polymer Nanoparticles Loading Copper(II) and Chlorambucil for Cooperative Chemodynamic/Chemotherapy.

Chemodynamic therapy (CDT) reflects an innovative cancer treatment modality; however, to enhance its relatively low therapeutic efficiency, rational combination with extra therapeutic modes is highly appreciated. Here, core-coordinated amphiphilic, elliptic polymer nanoparticles (Cu/CBL-POEGEA NPs) are constructed via the self-assembly of a glutathione (GSH)-responsive polymer-drug conjugate, bearing side-chain acylthiourea (ATU) motifs which behave as ligands capable of coordinating Cu(II), such a design is featured by combined chemo (CT)/CDT with dual GSH depletion collectively triggered by the Cu(II) reduction reaction and disulfide bond breakage. To do so, an amphiphilic random copolymer poly[oligo(ethylene glycol)ethyl acrylate-co-thiourea] [P(OEGEA-co-ATU)] is synthesized, followed by conjugation of chlorambucil (CBL) to ATU motifs linked via a disulfide bond, thus yielding the targeted P[OEGEA-co-(ATU-g-CBL)]. In such a system, hydrophilic POEGEA serves as the biocompatible section and ATU motifs coordinate Cu(II), resulting in core-coordinated elliptic Cu/CBL-POEGEA NPs. Benefitting from the GSH-induced reduction reaction, Cu(II) is converted into Cu(I) and subsequently react with endogenous H2O2 to create •OH, realizing GSH-depletion-promoted CDT. Additionally, the disulfide bond endows GSH-responsive CBL release and provokes further GSH decline, finally realizing combined CDT/CT toward enhancing antitumor outcomes, and in vitro as well as in vivo studies indeed reveal remarkable efficacy. Such a system can provide valuable advantages to create novel nanomedicines toward cascade antitumor therapy.