A Mechanically Resilient Soft Hydrogel Improves Drug Delivery for Treating Post-Traumatic Osteoarthritis in Physically Active Joints.

Intra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in early post-traumatic osteoarthritis (PTOA) when symptoms are minimal and patients are physically active. DMOAD delivery systems therefore must withstand repeated mechanical loading without affecting the drug release kinetics. Although soft materials are preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt drug release. Here, we report a mechanically resilient soft hydrogel that rapidly self-heals under conditions resembling human running while maintaining sustained release of the cathepsin-K inhibitor L-006235 used as a proof-of-concept DMOAD. Notably, this hydrogel outperformed a previously reported hydrogel designed for intra-articular drug delivery, used as a control in our study, which neither recovered nor maintained drug release under mechanical loading. Upon injection into mouse knee joints, the hydrogel showed consistent release kinetics of the encapsulated agent in both treadmill-running and non-running mice. In a mouse model of aggressive PTOA exacerbated by treadmill running, L-006235 hydrogel markedly reduced cartilage degeneration. To our knowledge, this is the first hydrogel proven to withstand human running conditions and enable sustained DMOAD delivery in physically active joints, and the first study demonstrating reduced disease progression in a severe PTOA model under rigorous physical activity, highlighting the hydrogel's potential for PTOA treatment in active patients.

Technetium-99m labeled core shell hyaluronate nanoparticles as tumor responsive, metastatic skeletal lesion targeted combinatorial theranostics.

Achieving target specific delivery of chemotherapeutics in metastatic skeletal lesions remains a major challenge. Towards this, a dual drug loaded, radiolabeled multi-trigger responsive nanoparticles having partially oxidized hyaluronate (HADA) conjugated to alendronate shell and palmitic acid core were developed. While the hydrophobic drug, celecoxib was encapsulated in the palmitic acid core, the hydrophilic drug, doxorubicin hydrochloride was linked to the shell via a pH responsive imine linkage. Hydroxyapatite binding studies showed affinity of alendronate conjugated HADA nanoparticles to bones. Enhanced cellular uptake of the nanoparticles was achieved via HADA-CD44 receptor binding. HADA nanoparticles demonstrated trigger responsive release of encapsulated drugs in the presence of hyaluronidase, pH and glucose, present in excess in the tumor microenvironment. Efficacy of the nanoparticles for combination chemotherapy was established by >10-fold reduction in IC50 of drug loaded particles with a combination index of 0.453, as compared to free drugs in MDA-MB-231 cells. The nanoparticles could be radiolabeled with the gamma emitting radioisotope technetium-99m (99mTc) through a simple, 'chelator free', procedure with excellent radiochemical purity (RCP) (>90 %) and in vitro stability. 99mTc-labeled drug loaded nanoparticles reported herein constitutes a promising theranostic agent to target metastatic bone lesions. STATEMENT OF HYPOTHESES: Technetium-99m labeled, alendronate conjugated, dual targeting, tumor responsive, hyaluronate nanoparticle for tumor specific drug release and enhanced therapeutic effect, with real-time in vivo monitoring.

Multifunctional Core-Shell Glyconanoparticles for Galectin-3-Targeted, Trigger-Responsive Combination Chemotherapy.

Galectin-3 (gal-3) plays a crucial role in various cellular events associated to tumor metastasis and progression. In this direction, gal-3 binding core-shell glyconanoparticles based on citrus pectin (CP) have been designed for targeted, trigger-responsive combination drug delivery. Depolymerization via periodate oxidation in heterogeneous medium yielded low-molecular weight dialdehyde oligomers (CPDA) of CP with a gal-3 binding property (Kd = 160.90 µM). CPDA-based core-shell nanoparticles prepared to enhance the gal-3 binding specificity via a multivalent ligand presentation have shown to reduce homotypic cellular aggregation, tumor cell binding with endothelial cells, and endothelial tube formation, the major steps involved in the progression of cancer. Immune-fluorescence and flow cytometric analysis confirmed significant reduction in gal-3 expression on MDA-MB 231 cancer cells upon incubation with nanoparticles. An on-demand tumor microenvironment-responsive release of drugs at low pH and high concentrations of glucose and glutathione prevailing in tumor milieu was achieved by introducing a cleavable Schiff's base, a boronate ester, and disulfide linkages within the shell of the nanoparticles. Nanoparticles with encapsulated sulindac in the core and doxorubicin (DOX) in the shell demonstrated target specificity and enhanced internalization with synergistic cytotoxic effects with a 30-fold reduction in IC50 in DOX-resistant, triple-negative MDA-MB 231 breast cancer cells. Nanoparticles were radiolabeled with 131I radioisotopes with ≥80% efficiency while retaining its gal-3 binding property. Biodistribution studies of radiolabeled placebo nanoparticles and drug-loaded CPDA nanoparticles demonstrated proof of concept of gal-3 targeting seen as preferential accumulation in the gal-3-expressing tissues of the gastric tract. The CPDA core-shell nanoparticles are thus promising platforms for gal-3 targeting and inhibition of gal-3-mediated processes involved in cancer progression with a potential of radiolabeling for in vivo monitoring or delivering therapeutic doses of radiation and on-demand triggered, target-specific drug release.

Inhalational Drug Delivery in Pulmonary Aspergillosis.

Pulmonary infections have long represented one of the major threats to humans. These vary from acute to chronic conditions, depending upon the underlying disease of the airways. Pulmonary aspergillosis (PMAP) has raised vital concerns in the immunocompromised patients. The fungal infection is difficult to diagnose in the early stages, often making the disease more complicated. Currently, three classes of antifungal agents are available on the market for the treatment of pulmonary infections. These agents are available in oral and intravenous forms only, which limits the availability of therapeutic concentrations of drug in the lungs for longer durations. Consequently, this leads to therapeutic failure and/or resistance of the organism(s) towards the antifungal agents because the optimum amount of drug does not reach the infection site. To combat the issues associated with the conventional regimens, inhalation of antifungal agents is gaining importance because administration to the lungs offers huge advantages of localized and targeted delivery. A wide range of inhalational devices such as nebulizers, dry powder inhalers, and metered dose inhalers are available on the market to deliver drug molecules to the lungs effectively. However, their clinical utility is limited to conditions such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis only. For a few decades, inhalation therapy has also been gaining importance to treat infectious diseases such as tuberculosis and aspergillosis, though more research efforts are required to make the transition from bench to bedside. The current review provides an explicit account of the potential role of inhalation drug delivery in PMAP.

Advances in Sub-Micron Particle Based Aerosol Strategies for Efficient Systemic Delivery of Therapeutic Agents.

BACKGROUND: Over the past few decades, the field of nanotechnology has led to significant advances in healthcare, impacting both diagnosis and therapy. Systemic delivery of therapeutics via inhalation route has also advanced with the use of sub micron particles as colloidal drug carriers. Use of inhalable nanocarriers for delivering drugs systemically offers additional degree of control and manipulation, thereby maximizing the alveolar deposition and minimizing clearance. The ramifications are improved systemic absorption and higher therapeutic efficacy. Herein, we review the progress and advances related to nanoparticle based inhalable formulations for systemic delivery of therapeutics, and also discusses the associated challenges. METHODS: We performed detailed searches in PubMed and compiled the literature on inhalable nanoparticles for systemic delivery of therapeutic agents. RESULTS: To date, multiple inhalable nanocarriers have been explored for systemic delivery of therapeutics; and can be broadly classified into three categories, viz. lipid based nanoparticles, polymeric nanoparticles and porous nanoparticle aggregate particles. CONCLUSION: In spite of the promising data, there are still multiple challenges, including poor understanding of nanotoxicology of therapeutic nanoparticles. Overcoming these challenges can lead to successful clinical translation of inhalable nanoparticles for systemic drug delivery, leading to the development of more effective and patient compliant therapies.

Trigger responsive polymeric nanocarriers for cancer therapy.

Conventional chemotherapy for the treatment of cancer has limited specificity when administered systemically and is often associated with toxicity issues. Enhanced accumulation of polymeric nanocarriers at a tumor site may be achieved by passive and active targeting. Incorporation of trigger responsiveness into these polymeric nanocarriers improves the anticancer efficacy of such systems by modulating the release of the drug according to the tumor environment. Triggers used for tumor targeting include internal triggers such as pH, redox and enzymes and external triggers such as temperature, magnetic field, ultrasound and light. While internal triggers are specific cues of the tumor microenvironment, external triggers are those which are applied externally to control the release. This review highlights the various strategies employed for the preparation of such trigger responsive polymeric nanocarriers for cancer therapy and provides an overview of the state of the art in this field.