Responsive Microneedles for Diagnostic and Therapeutic Applications of Ocular Diseases.

Traditional ophthalmic formulations are characterized by low bioavailability, short intraocular retention time, strong irritation, and failure to achieve the expected therapeutic effect due to the special physiological structure of the eye and the existence of many barriers. Microneedle drug delivery is a novel transdermal drug delivery modality. Responsive microneedles are defined as controllably releasing the drug payloads in response to physiological stimuli, including pH levels, temperature, enzymes, and reactive oxygen species (ROS), as well as external stimuli such as magnetic fields and light.

ROS-Responsive Microneedle Patches Enable Peri-Lacrimal Gland Therapeutic Administration for Long-Acting Therapy of Sjögren's Syndrome-Related Dry Eye.

Sjögren's syndrome-related dry eye (SSDE) is a severe dry eye subtype characterized by significant immune cell attacks on the lacrimal gland. However, delivering immunosuppressive drugs to the lacrimal glands for SSDE therapy safely and sustainably poses significant challenges in clinical practice. Herein, a ROS-responsive microneedle patch with detachable functionality (CE-MN) is developed to enable straightforward and minimally invasive administration to the lacrimal gland area by penetrating the periocular skin.

Tumor-penetrating iRGD facilitates penetration of poly(floxuridine-ketal)-based nanomedicine for enhanced pancreatic cancer therapy.

Efficient intratumoral penetration is essential for nanomedicine to eradicate pancreatic tumors. Although nanomedicine can enter the perivascular space of pancreatic tumors, their access to distal tumor cells, aloof from the vessels, remains a formidable challenge. Here, we synthesized an acid-activatable macromolecular prodrug of floxuridine (FUDR)-poly(FUDR-ketal), engineered a micellar nanomedicine of FUDR, and intravenously co-administered the nanomedicine with the tumor-penetrating peptide iRGD for enhanced treatment of pancreatic tumor.

Type I Collagen-Adhesive and ROS-Scavenging Nanoreactors Enhanced Retinal Ganglion Cell Survival in an Experimental Optic Nerve Crush Model.

Traumatic optic neuropathy (TON) is a severe condition characterized by retinal ganglion cell (RGC) death, often leading to irreversible vision loss, and the death of RGCs is closely associated with oxidative stress. Unfortunately, effective treatment options for TON are lacking. To address this, catalase (CAT) is encapsulated in a tannic acid (TA)/poly(ethylenimine)-crosslinked hollow nanoreactor (CAT@PTP), which exhibited enhanced anchoring in the retina due to TA-collagen adhesion.

Drug content on anticancer efficacy of self-assembling ketal-linked dextran-paclitaxel conjugates.

Although polymer-drug conjugates (PDCs) show great promise as versatile drug delivery systems, no antitumor PDCs based on small-molecule drugs are currently on the market, partly because of the lack of validated design principles for PDCs. High drug content is thought to be essential for devising highly efficacious PDCs based on poorly soluble antitumor drugs, but this has not been well validated. Therefore, revisiting the relationship between drug content and PDC performance is vital.

Fine-tuning the sequential drug release of nano-formulated mutual prodrugs dictates the combination effects.

The maintenance of robust ratiometric loading of dual therapeutic agents and fine-tuning release kinetics for consistent and optimization of combination effects is vital for discovering new anticancer drug combinations and remains challenging. Smart nanomedicine strategies have been investigated for this purpose, but most of the reported strategies focus either on ratiometric delivery or on unimodal sequential release of the two different agents, which hampers effective optimization of combination effects. Herein we report a sequential drug release system based on nanoformulated mutual prodrugs constructed by the formation of ketal linkages with different acid sensitivities, thus enabling the acid-triggered release of two anticancer drugs, paclitaxel and gemcitabine, in various sequences.

Stromal Homeostasis-Restoring Nanomedicine Enhances Pancreatic Cancer Chemotherapy.

The desmoplastic stroma imposes a fatal physical delivery barrier in pancreatic ductal adenocarcinoma (PDAC) therapy. Deconstructing the stroma components hence predominates in stroma-targeting approaches, but conflicting outcomes have sometimes occurred due to the multifaceted nature of the stroma. Here, we constructed two sub-20-nm nanomedicines based on a so-called "next-wave" antifibrotic halofuginone (HF) and the tumoricidal paclitaxel (PTX) for enhanced PDAC chemotherapy.

Modular ketal-linked prodrugs and biomaterials enabled by organocatalytic transisopropenylation of alcohols.

Isopropenyl ethers are critical intermediates for accessing medicinally valuable ketal-based prodrugs and biomaterials, but traditional approaches for the synthesis of isopropenyl ethers suffer from poor functional group compatibility and harsh reaction conditions. Here, we develop an organocatalytic transisopropenylation approach to solve these challenges, enabling the synthesis of isopropenyl ethers from various hydroxyl-group-containing small-molecule drugs, polymers, and functional building blocks. The method provides a straightforward and versatile synthesis of isopropenyl ethers, features excellent tolerance of diverse functional groups, applies to a wide range of substrates, and allows scalable synthesis.

Acid-sensitive PEGylated paclitaxel prodrug nanoparticles for cancer therapy: Effect of PEG length on antitumor efficacy.

Paclitaxel is one of the most widely used anticancer agents, but strong side effects and low bioavailability limit its clinical efficacy. The use of tumor microenvironment-responsive prodrugs is promising to solve these problems, and a smart linkage is crucial to achieve the efficient release of paclitaxel from such prodrugs in tumor. Herein, an acid-responsive acetone-based acyclic ketal linkage is used to construct paclitaxel prodrugs with different length of poly(ethylene glycol) (PEG).

Modular Acid-Activatable Acetone-Based Ketal-Linked Nanomedicine by Dexamethasone Prodrugs for Enhanced Anti-Rheumatoid Arthritis with Low Side Effects.

Given the physically encapsulated payloads with drug burst release and/or low drug loading, it is critical to initiate an innovative prodrug strategy to optimize the design of modular nanomedicines. Here, we designed modular pH-sensitive cetone-based etal-linked rodrugs of amethasone (AKP-dexs) and formulated them as nanoparticles. We comprehensively studied the relationships between AKP-dex structure and properties, and we selected two types of AKP-dex-loaded nanoparticles for in vivo studies on the basis of their size, drug loading, and colloidal stability.

Acid-Triggered Release of Native Gemcitabine Conjugated in Polyketal Nanoparticles for Enhanced Anticancer Therapy.

Nucleoside analogue drugs are widely used in cancer therapy and antiviral therapy, while fast metabolism, drug resistance, and severe side effects significantly limit their clinical applications. To address these issues, a variety of ester- and amide-linked prodrugs and their nanoparticulate formulations have been devised. However, most of these prodrugs suffer from inefficient transformation to native drugs in tumor.

Simultaneous determination of phenolic acids and diterpenoids and their comparative pharmacokinetic study in normal and acute blood stasis rats by UFLC-MS/MS after oral administration of Guan-Xin-Shu-Tong capsules.

Guan-Xin-Shu-Tong capsules are one of the well-known and first-line Chinese traditional herbal formula for treating coronary heart disease. A validated and sensitive method via ultra fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) was established to simultaneously determinate five phenolic acids and four diterpenoids in rats in order to investigate their pharmacokinetic profiles firstly. Analytes were extracted by ethyl acetate and determined via multiple reaction monitoring mode in both positive and negative ion modes.

Vortex-ultrasound-assisted dispersive liquid-liquid microextraction coupled with gas chromatography-mass spectrometry for the analysis of volatile bioactive components and comparative pharmacokinetic study of the herb-herb interactions in Guanxin Shutong Capsule.

Guanxin Shutong Capsule, an effective traditional Chinese medicine, is widely used for coronary heart disease clinically. Volatile components are one of its important bioactive constituents. To better understand the material basis for the therapeutic effects, the components of Guanxin Shutong Capsule absorbed into the blood and their metabolites were identified based on gas chromatography with mass spectrometry coupled with vortex-ultrasound-assisted dispersive liquid-liquid microextraction.

Comprehensive Identification of Guan-Xin-Shu-Tong Capsule via a Mass Defect and Fragment Filtering Approach by High Resolution Mass Spectrometry: In Vitro and In Vivo Study.

The Guan-Xin-Shu-Tong capsule (GXSTC) is a well-known traditional Chinese medicine that is used for the treatment of coronary heart disease. Despite its common use in China, basic pharmacological research on its active components is limited. A comprehensive analytical method using quadrupole-time-of-flight mass spectrometry (Q-TOF/MS), specifically with the Triple TOF 5600 platform, was developed to characterize the compounds in the GXSTC powder itself (in vitro) as well as the active components in healthy and heart disease model rats after its oral administration (in vivo).