Glycol chitosan stabilized nanomedicine of lapatinib and doxorubicin for the management of metastatic breast tumor.

Advanced breast cancer is known to be highly evasive to conventional therapeutic regimes with a 5-year survival rate of less than 30% compared to over 90% for early stages. Although several new approaches are being explored to improve the survival outcome, there is still some room for equipping existing drugs such as lapatinib (LAPA) and doxorubicin (DOX) to fight the systemic disease. LAPA is associated with poorer clinical outcomes in HER2-negative patients. However its ability to also target EGFR has warranted its use in recent clinical trials. Nevertheless, the drug is poorly absorbed post oral administration and possess low aqueous solubility. DOX on the other hand is avoided in vulnerable patients in advanced stages due to its pronounced off-target toxicity. To overcome the pitfalls of the drugs, we have fabricated a nanomedicine co-loaded with LAPA & DOX and stabilized with glycol chitosan, a biocompatible polyelectrolyte. With a loading content of ~ 11.5% and ~ 15% respectively, LAPA and DOX in a single nanomedicine showed synergistic action against triple-negative breast cancer cells in comparison to physically mixed free drugs. The nanomedicine showed a time-dependent association with cancer cells thereon inducing apoptosis leading to ~ 80% cell death. The nanomedicine was found to be acutely safe in healthy Balb/c mice and could negate DOX-induced cardio toxicity. The combination nanomedicine significantly inhibited both the primary 4T1 breast tumor and its spread to the lung, liver, heart, and kidney compared to pristine drug controls. These preliminary data indicate bright prospects for the nanomedicine to be effective against metastatic breast cancer.

Nanoemulsified Genistein and Vitamin D Mediated Epigenetic Regulation to Inhibit Osteoporosis.

The imbalance in the bone remodeling process with more bone resorption by osteoclasts compared to bone formation by osteoblasts results in a metabolic bone disorder known as osteoporosis. This condition reduces the bone mineral density and increases the risk of fractures due to low bone mass and disrupted bone microarchitecture. Osteoclastogenesis increases when the receptor activator NFκB ligand (RANKL) on the osteoblast surface binds to the receptor activator NFκB (RANK) on the osteoclast surface and the function of the decoy receptor of RANKL, osteoprotegrin, is compromised due to external stimuli such as heparin and lipopolysaccharides. The RANK/RANKL axis promotes the nuclear factor kappa B (NFκB) expression, which in turn increases the histone methyltransferase activity of EzH2 and EzH1 for the epigenetic regulation of osteoclastogenesis-related genes. Genistein counteracts NFκB-induced osteoclastogenesis and downstream signaling through the direct regulation of histone methyltransferase, EzH2 and EzH1, transcription. However, genistein possesses limitations like low bioavailability, low water solubility, high estrogen activity, and thyroid side effects, which obstruct its therapeutic usage. Here, the nanoemulsified formulation of genistein with vitamin D was utilized to circumvent the limitations of genistein so that it can be utilized for therapeutic purposes in osteoporosis management. The nanoemulsification of genistein and vitamin D was performed through the spontaneous emulsification using Tween 80 and medium chain triglyceride oil as an organic phase. The physiologically stable and biocompatible combination of the genistein and vitamin D nanoemulsion (GVNE) exhibited the controlled release pattern of genistein with Korsmeyer-Peppas and Higuchi models under different pH conditions (7.4, 6.5, and 1.2). The GVNE potentially enhanced the therapeutic efficacy under in vitro osteoporosis models and helped restore disease parameters like alkaline phosphatase activity, tartrate-resistant acid phosphatase activity, and the formation of multinuclear giant cells. Molecularly, the GVNE overturned the LPS-induced osteoclastogenesis by downregulation of NFκB expression along with its binding on EzH2 and EzH1 promoters. GVNE effects on the osteoporosis model established it as an efficient antiosteoporotic therapy. This nanonutraceutical-based formulation provides an epigenetic regulation of osteoporosis management and opens new avenues for alternate epigenetic therapies for osteoporosis.