Chemotaxis-guided Self-propelled Macrophage Motor for Targeted Treatment of Acute Pneumonia.

Immune cells exhibit great potential as carriers of nanomedicine, attributed to their high tolerance to internalized nanomaterials and targeted accumulation in inflammatory tissues. However, the premature efflux of internalized nanomedicine during systemic delivery and slow infiltration into inflammatory tissues have limited their translational applications. Herein, a motorized cell platform as a nanomedicine carrier for highly efficient accumulation and infiltration in the inflammatory lungs and effective treatment of acute pneumonia are reported. ß-Cyclodextrin and adamantane respectively modified manganese dioxide nanoparticles are intracellularly self-assembled into large aggregates mediated via host-guest interactions, to effectively inhibit the efflux of nanoparticles, catalytically consume/deplete H2 O2 to alleviate inflammation, and generate O2 to propel macrophage movement for rapid tissue infiltration. With curcumin loaded into MnO2 nanoparticles, macrophages carry the intracellular nano-assemblies rapidly into the inflammatory lungs via chemotaxis-guided, self-propelled movement, for effective treatment of acute pneumonia via immunoregulation induced by curcumin and the aggregates.

Supramolecular micelles as multifunctional theranostic agents for synergistic photodynamic therapy and hypoxia-activated chemotherapy.

Photodynamic therapy (PDT), where a photosensitizer (under light irradiation) converts molecular oxygen to singlet oxygen to elicit programmed cell death, is a promising cancer treatment modality with a high temporal and spatial resolution. However, only limited cancer treatment efficacy has been achieved in clinical PDT due to the hypoxic conditions of solid tumor microenvironment that limits the generation of singlet oxygen, and PDT process often leads to even more hypoxic microenvironment due to the consumption of oxygens during therapy. Herein, we designed novel supramolecular micelles to co-deliver photosensitizer and hypoxia-responsive prodrug to improve the overall therapeutic efficacy. The supramolecular micelles (CPC) were derived from a polyethylene glycol (PEG) system dually tagged with hydrophilic cucurbit[7]uril (CB[7]) and hydrophobic Chlorin e6 (Ce6), respectively on each end, for synergistic antitumor therapy via PDT of Ce6 and chemotherapy of a hypoxia-responsive prodrug, banoxantrone (AQ4N), loaded into the cavity of CB[7]. In addition, CPC was further modularly functionalized by folate (FA) via strong host-guest interaction between folate-amantadine (FA-ADA) and CB[7] to produce a novel nanoplatform, AQ4N@CPC-FA, for targeted delivery. AQ4N@CPC-FA exhibited enhanced cellular uptake, negligible cytotoxicity and good biocompatibility, and improved intracellular reactive oxygen species (ROS) generation efficiency. More importantly, in vivo evaluation of AQ4N@CPC-FA revealed a synergistic antitumor efficacy between PDT of Ce6 and hypoxia-activated chemotherapy of AQ4N (that can be converted to chemotherapeutic AQ4 for tumor chemotherapy in response to the strengthened hypoxic tumor microenvironment during PDT treatment). This study not only provides a new nanoplatform for synergistic photodynamic-chemotherapeutic treatment, but also offers important new insights to design and development of multifunctional supramolecular drug delivery system. STATEMENT OF SIGNIFICANCE: Photodynamic therapy (PDT) has exhibited a variety of advantages for cancer phototherapy as compared to traditional chemotherapy. However, the unsatisfactory therapeutic efficacy by PDT alone as a result of the enhanced tumor hypoxia during PDT has limited its clinical application. Herein, we designed multifunctional supramolecular micelles to co-deliver photosensitizer and hypoxia-responsive prodrug to improve the overall therapeutic efficacy. The supramolecular micelles are biocompatible and possess strong red absorption, controlled drug release profile, and ultimately enhanced therapeutic outcome via PDT-chemotherapy. This study not only provides a new nanoplatform for synergistic photodynamic-chemotherapeutic treatment of cancer, but also offers important new insights to design and development of multifunctional supramolecular drug delivery tool for multi-modality cancer therapy.

Oral Colon-Targeted Konjac Glucomannan Hydrogel Constructed through Noncovalent Cross-Linking by Cucurbit[8]uril for Ulcerative Colitis Therapy.

Orally administered colon-targeted formulations of drugs are of great importance in managing diseases in the colon. However, it is often challenging to maintain the integrity of such formulations during delivery, particularly in the gastric environment, which may lead to premature drug release before reaching the targeted colon. Herein, an oral colon-targeted drug delivery hydrogel (OCDDH) was developed through cucurbit[8]uril (CB[8])-mediated noncovalent cross-linking of phenylalanine (Phe)-modified Konjac glucomannan (KGM), in which berberine (BBR), a natural anti-inflammatory product originating from Chinese medicine, was loaded into the hydrogel matrix. With the strong host-guest complexation mediated cross-linking and the inherent reversibility of such interactions, KGM-Phe@CB[8] hydrogel exhibited a readily tunable degree of cross-linking and an excellent self-healing capability, and therefore the hydrogel retained ultrahigh stability in the gastric environment, which is important for orally administered formulations to target the colon. In the colon, KGM may get degraded by colon-specific enzymes, ß-mannanase or ß-glucosidase, resulting in burst release of the loaded cargoes on site. The structure and specific payload release of the hydrogel, with and without BBR, have been fully characterized in vitro, and the therapeutic effect of BBR-loaded KGM-Phe@CB[8] hydrogel was evaluated against dextran sulfate sodium (DSS) induced ulcerative colitis (UC) in a mouse model. Very interestingly, the BBR-loaded KGM-Phe@CB[8] hydrogel exhibited significantly improved therapeutic efficacy in treating colitis, without causing any systemic toxicity, when compared with free BBR. This strategy may pave a new way in the development of advanced supramolecular OCDDH.