Oral liposomal delivery of an activatable budesonide prodrug reduces colitis in experimental mice.

Inflammatory bowel disease (IBD) is one of the most common intestinal disorders, with increasing global incidence and prevalence. Numerous therapeutic drugs are available but require intravenous administration and are associated with high toxicity and insufficient patient compliance. Here, an oral liposome that entraps the activatable corticosteroid anti-inflammatory budesonide was developed for efficacious and safe IBD therapy. The prodrug was produced via the ligation of budesonide with linoleic acid linked by a hydrolytic ester bond, which was further constrained into lipid constituents to form colloidal stable nanoliposomes (termed budsomes). Chemical modification with linoleic acid augmented the compatibility and miscibility of the resulting prodrug in lipid bilayers to provide protection from the harsh environment of the gastrointestinal tract, while liposomal nanoformulation enables preferential accumulation to inflamed vasculature. Hence, when delivered orally, budsomes exhibited high stability with low drug release in the stomach in the presence of ultra-acidic pH but released active budesonide after accumulation in inflamed intestinal tissues. Notably, oral administration of budsomes demonstrated favorable anti-colitis effect with only ∼7% mouse body weight loss, whereas at least ∼16% weight loss was observed in other treatment groups. Overall, budsomes exhibited higher therapeutic efficiency than free budesonide treatment and potently induced remission of acute colitis without any adverse side effects. These data suggest a new and reliable approach for improving the efficacy of budesonide. Our in vivo preclinical data demonstrate the safety and increased efficacy of the budsome platform for IBD treatment, further supporting clinical evaluation of this orally efficacious budesonide therapeutic.

Photoactivatable nanoagonists chemically programmed for pharmacokinetic tuning and in situ cancer vaccination.

Immunotherapy holds great promise for the treatment of aggressive and metastatic cancers; however, currently available immunotherapeutics, such as immune checkpoint blockade, benefit only a small subset of patients. A photoactivatable toll-like receptor 7/8 (TLR7/8) nanoagonist (PNA) system that imparts near-infrared (NIR) light-induced immunogenic cell death (ICD) in dying tumor cells in synchrony with the spontaneous release of a potent immunoadjuvant is developed here. The PNA consists of polymer-derived proimmunoadjuvants ligated via a reactive oxygen species (ROS)-cleavable linker and polymer-derived photosensitizers, which are further encapsulated in amphiphilic matrices for systemic injection. In particular, conjugation of the TLR7/8 agonist resiquimod to biodegradable macromolecular moieties with different molecular weights enabled pharmacokinetic tuning of small-molecule agonists and optimized delivery efficiency in mice. Upon NIR photoirradiation, PNA effectively generated ROS not only to ablate tumors and induce the ICD cascade but also to trigger the on-demand release of TLR agonists. In several preclinical cancer models, intravenous PNA administration followed by NIR tumor irradiation resulted in remarkable tumor regression and suppressed postsurgical tumor recurrence and metastasis. Furthermore, this treatment profoundly shifted the tumor immune landscape to a tumoricidal one, eliciting robust tumor-specific T cell priming in vivo. This work highlights a simple and cost-effective approach to generate in situ cancer vaccines for synergistic photodynamic immunotherapy of metastatic cancers.

Ultrasmall organosilica nanoparticles with strong solid-state fluorescence for multifunctional applications.

INTRODUCTION: Organosilica nanoparticles (ONs), which are a new type of photoluminescent nanomaterial (PM) with excellent biocompatibility, have caught more attention in recent years. However, their applications are significantly impeded by the complicated preparation process, poor photostability, and especially aggregation-induced quenching. OBJECTIVES: The present study was aimed to design and prepare solid-state fluorescent ONs to avoid aggregation-induced quenching effect. In addition, the uses of ONs for fingerprint detection, white light-emitting diodes (WLEDs) and lysosome-targetable cellular imaging were demonstrated. METHODS: Here, for the first time, we designed and prepared novel solid-state fluorescent ultrasmall ONs with orange-emitting photoluminescence via a one-step hydrothermal method. RESULTS: The prepared solid-state fluorescent ONs could be successfully employed in fingerprint detection, WLEDs fabrication and cellular imaging. Intriguingly, the ultrasmall ONs specifically localized to lysosomes rather than other subcellular organelles across distinct cell lines, including cancer cells and noncancerous cells. CONCLUSION: Collectively, these data showed that the new ONs presented in this study could be ideal candidates for PMs in biological and photoelectric applications.

De novo engineering of both an omega-3 fatty acid-derived nanocarrier host and a prodrug guest to potentiate drug efficacy against colorectal malignancies.

Drug-carrier compatibility impacts drug delivery efficiency and resulting therapeutic efficacy and tolerability. Although numerous biodegradable carrier materials have been pursued over the past decades, chemical strategies that are sought to tailor therapeutic structures and their carriers together in a concerted effort remain rare yet may be powerful. Based on the principle of improving the structural similarity between these central components, we developed an omega-3 fatty acid-conjugated poly(ethylene glycol) (PEG) nanocarrier host that is capable of supramolecular assembly of a cytotoxic prodrug guest. To demonstrate the proof of concept, we ligated two docosahexaenoic acid (DHA) molecules and one PEG chain via a d-lysine linkage to produce an amphiphilic matrix DHA2-PEG, which is suited for the encapsulation of active compounds, including a DHA monoconjugated camptothecin prodrug. The resulting DHA2-PEG-cloaked nanoassemblies show superior stability and rapid cellular uptake compared with those formulated in clinically approved materials. In a chemically induced mouse model of colitis-associated colorectal cancer, administration of the camptothecin nanoassemblies demonstrated notable inhibition of colon tumor growth. Furthermore, this new delivery platform has low systemic toxicity and immunotoxicity in animals and is appealing for further investigation and clinical translation. Thus, through rational engineering of the carrier biomaterials and drug derivatization, the in vivo performance of drug delivery systems can be improved. This approach also establishes a methodology for leveraging synthetic chemistry tools to optimize delivery systems for a broad range of drug classes.

A Renally Clearable Activatable Polymeric Nanoprobe for Early Detection of Hepatic Ischemia-Reperfusion Injury.

Although hepatic ischemia-reperfusion injury (IRI) represents a major complication in many clinical settings, it remains a diagnostic dilemma due to its reliance on insensitive assays or invasive biopsy. The development of an activatable polymeric nanoprobe (APNSO ) for real-time in vivo near-infrared fluorescence (NIRF) imaging and urinalysis of hepatic IRI is reported here. APNSO has a backbone comprising renally clearable fluorophore fragments and self-immolative structural units. In the presence of an oxidative stress biomarker (superoxide anion, O2 •- ) during hepatic IRI, APNSO can be fluorescently activated for in vivo NIRF imaging and depolymerized to release renally clearable fluorophores for urinalysis. By virtue of its high hepatic accumulation, sensitive response toward O2 •- , and effective release of renally clearable fluorophores, APNSO -based imaging and urinalysis detect hepatic IRI at least 7 h earlier than typical clinical assays in a mouse model. This study not only provides new opportunities for noninvasive diagnosis of hepatic IRI, but also reveals guidelines for the development of optical nanosensors for early urinalysis.