Nanomedicine for Drug Delivery throughout the Alimentary Canal.

The field of nanomedicine continues to grow with new technologies and formulations in development for several disease states. Much research focuses on the use of injectable nanomedicines for treatment of neoplasms; however, there are several formulations in development that use nanotechnology that can be administered enterally for noncancer indications. These nanomedicine treatments have been developed for systemic drug delivery or local drug delivery along the gastrointestinal tract. This Review gives a brief overview of the alimentary canal and highlights new research in nanomedicine in noncancer disease states delivered via enteral routes of administration. Relevant recent research is summarized on the basis of the targeted site of action or absorption, including the buccal, sublingual, stomach, small intestine, and large intestine areas of the alimentary canal. The benefits of nanodrug delivery are discussed as well as barriers and challenges for future development in the field.

Mechanistic Basis for the Role of Phytochemicals in Inflammation-Associated Chronic Diseases.

Chronic inflammatory diseases occur in a large portion of the population and are associated with a poor diet. Key natural products found in fruits and vegetables may assist in lowering inflammation associated with chronic diseases such as obesity, diabetes, cardiovascular diseases, and cancer. This review seeks to examine the roles of several natural products, resveratrol (RES), quercetin (QUE), curcumin (CUR), piperine (PIP), epigallocatechin gallate (EGCG), and gingerol (GIN), in their ability to attenuate inflammatory markers in specific diseases states. Additionally, we will discuss findings in past and ongoing clinical trials, detail possible phytochemical-drug interactions, and provide a brief resource for researchers and healthcare professionals on natural product and supplement regulation as well as names of databases with information on efficacy, indications, and natural product-drug interactions. As diet and over-the-counter supplement use are modifiable factors and patients are interested in using complementary and alternative therapies, understanding the mechanisms by which natural products have demonstrated efficacy and the types of drugs they interact with and knowing where to find information on herbs and supplements is important for practicing healthcare providers and researchers interested in this field.

Chemosensitization and mitigation of Adriamycin-induced cardiotoxicity using combinational polymeric micelles for co-delivery of quercetin/resveratrol and resveratrol/curcumin in ovarian cancer.

This work looks to improve the efficacy of Adriamycin (ADR) while mitigating its cardiotoxicity using combinations of micellar resveratrol (R): quercetin (Q) (mRQ) or R: curcumin (C) (mRC) in healthy mice and ovarian cancer xenograft models. Ovarian cancer cells, ES2-Luc, or A2780ADR are inoculated in mice (n =4/group) and sorted into eight cohorts. Mice are treated weekly for 4 weeks with ADR, ADR+mRQ, ADR+mRC, or controls (saline, empty micelles, ADR+EM, mRQ, or mRC). To evaluate the degree of cardioprotection, serum is collected to determine the cardiac Troponin I (cTnI). Cardiac tissue is collected for morphological evaluation and evaluation of creatine kinase levels. Our results indicate that mRQ+ADR is statistically significant in tumor reduction in xenograft models. In healthy mice, the left ventricular ejection fraction and fractional shortening in the ADR treated group is most compromised. Co-administration of mRQ with ADR can reduce ADR dosing through chemosensitization while being cardioprotective.

Liposomes produced by microfluidics and extrusion: A comparison for scale-up purposes.

Successful liposomal formulations in the clinic are severely limited due to poor translational capability of the traditional bench techniques to clinical production settings. The gold standard for liposome bench manufacturing is a multi-step and parameter dependent extrusion method. Moreover, these parameters need re-optimization for clinical production. The microfluidics technique utilizes vigorous mixing of fluids at a nanoliter scale to produce liposomes in batches from milliliters to a couple liters. The fine control of process parameters results in improved reproducibility between batches. It is inherently scalable; however, the characteristics of liposomes produced by microfluidics both in vitro and in vivo have never been compared to those produced using extrusion. In this manuscript, we describe the comparison between the traditional extrusion method to microfluidics, the new paradigm in liposome production and scale-up.

Synthesis and characterization of new curcumin derivatives as potential chemotherapeutic and antioxidant agents.

The purpose of this work was to synthesize a series of symmetrical analogs (CA2-CA7) of curcumin and determine their efficacy as antioxidant and anticancer agents in vitro. The six analogs were successfully synthesized and characterized, one of which, CA6, had not been previously reported in the literature. With the exception of CA2, the analogs had lower predicted aqueous solubilities and higher partition coefficients than curcumin. Two analogs, CA2 and CA3, had lower potencies as anticancer agents compared with curcumin, while CA6 had a slightly higher IC50 value. Two different trends in the antioxidant capabilities of curcumin and its analogs were determined when assessed in vitro or in cell culture. The in vitro DPPH assay clearly showed curcumin as the strongest antioxidant as compared with the analogs when tested at the same concentration or at their IC50 value. The cell culture-based reactive oxygen species/reactive nitrogen species assay indicated that CA3 and CA6 were equal to curcumin in their free radical scavenging ability at the same concentration, but when curcumin and its analogs were tested at their respective IC50 values, CA4 and CA5 showed excellent antioxidant capacities. These results indicate that in cell culture, the ability of these analogs to produce antioxidant effects may be tied to their downstream effects.

Lymphatic changes in cancer and drug delivery to the lymphatics in solid tumors.

Although many solid tumors use the lymphatic system to metastasize, there are few treatment options that directly target cancer present in the lymphatic system, and those that do are highly invasive, uncomfortable, and/or have limitations. In this review we provide a brief overview of lymphatic function and anatomy, discusses changes that befall the lymphatics in cancer and the mechanisms by which these changes occur, and highlight limitations of lymphatic drug delivery. We then go on to summarize relevant techniques and new research for targeting cancer populations in the lymphatics and enhancing drug delivery intralymphatically, including intralymphatic injections, isolated limb perfusion, passive nano drug delivery systems, and actively targeted nanomedicine.

The Use and Utility of Low-dose Naltrexone Capsules for Patients with Fibromyalgia.

Fibromyalgia is a syndrome associated with chronic, widespread musculoskeletal pain, fatigue, depression, and cognitive dysfunction. With few U.S. Food and Drug Administration-approved treatment options, there is evidence that low-dose naltrexone, an opioid antagonist approved for opioid and alcohol dependence at high doses, may have efficacy in the treatment of fibromyalgia and chronic pain. At the doses required for fibromyalgia treatment, naltrexone needs to be compounded, and no data currently exists regarding the long-term stability of low-dose naltrexone capsules. This limits pharmacies to a maximum beyond-use date of 180 days. Our study examined the stability of compounded capsules of low-dose naltrexone in Avicel over 360 days. Naltrexone was extracted from compounded capsules and assessed using reversed-phase high-performance liquid chromatography validated to differentiate between the degraded and undegraded naltrexone. United States Pharmacopeia guidelines state that compounded medications must remain within 10% of the labeled potency at all times during the assigned expiration date for a preparation. Our results show that low-dose naltrexone is stable for 360 days when stored at room temperature and away from light remaining within 90% to 110% of the labeled potency throughout the study period. Based on our study results, the beyond-use date for compounded low-dose naltrexone formulations stored at room temperature and protected from light can be extended to 1 year. The longer beyond-use dating allows patients greater flexibility in using these capsules during the flare-ups associated with fibromyalgia without needing a refill immediately at the onset of symptoms. In addition, it may help compounding pharmacies reduce waste associated with small-batch preparation of these capsules.

Liposomal formulation of hypoxia activated prodrug for the treatment of ovarian cancer.

In this work, a new sphingomyelin-cholesterol liposomal formulation (CPD100Li) for the delivery of a hypoxia activated prodrug of vinblastine, mon-N-oxide (CPD100), is developed. The optimized liposomal formulation uses an ionophore (A23187) mediated pH-gradient method. Optimized CPD100Li is characterized for size, drug loading, and stability. The in vitro toxicity of CPD100Li is assessed on different aspects of cell proliferation and apoptosis of ES2 ovarian cancer under normoxic and hypoxic conditions. The pharmacokinetics of CPD100Li in mice as well as the influence of A23187 on the retention of CPD100 are assessed. The dose limiting toxicity (DLT) and maximum tolerated dose (MTD) for CPD100Li are evaluated in nude mice. CPD100 is loaded in the liposome at 5.5 mg/mL. The sizes of CPD100Li using DLS, qNano and cryo-TEM techniques are 155.4 ±â€¯4.2 nm, 132 nm, and 112.6 ±â€¯19.8 nm, respectively. There is no difference between the in vitro characterization of CPD100Li with and without ionophore. Freshly prepared CPD100Li with ionophore are stable for 48 h at 4 °C, while the freeze-dried formulation is stable for 3 months under argon at 4 °C. The hypoxic cytotoxicity ratios (HCR) of CPD100 and CPD100Li are 0.16 and 0.11, respectively. CPD100Li under hypoxic conditions has a 9.2-fold lower IC50 value as compared to CPD100Li under normoxic conditions, confirming the hypoxia dependent activation of CPD100. CPD100Li treated ES2 cells show a time dependent enhanced cell death, along with caspase production and an increase in the number of cells in G0/G1 and higher cell arrest. The blood concentration profile of CPD100Li in mice without A23187 has a 12.6-fold lower area under the curve (AUC) and 1.6-fold lower circulation time compared to the CPD100Li with A23187. The DLT for both CPD100 and CPD100Li is 45 mg/kg and the MTD is 40 mg/kg in nude mice. Based on the preliminary data obtained, we clearly show that the presence of ionophore affects the in vivo stability of CPD100. CPD100Li presents a unique opportunity to develop a first-in-kind chemotherapy product based on achieving selective drug activation through the hypoxic physiologic microenvironment of solid tumors.

Combinatorial resveratrol and quercetin polymeric micelles mitigate doxorubicin induced cardiotoxicity in vitro and in vivo.

Doxorubicin hydrochloride (ADR) is an anthracycline antibiotic used to treat various cancers. However, due to its extensive cardiotoxic side effects a lifetime cumulative dose limit of 450-550 mg/m2 exists. The postulated mechanism of the cardiotoxicity is generation of reactive oxygen and nitrogen species. Natural products like resveratrol (RES), and quercetin (QUE) are known free radical scavengers and have shown cardioprotective effects. However, concurrent dosing of these natural products with ADR is limited due to their low solubility, and low oral bioavailability. We hypothesize that the combination of RES and QUE in Pluronic® F127 micelles (mRQ) when co-administered with ADR, will be cardioprotective in vitro and in vivo, while maintaining or increasing the efficacy of ADR against cancer cell lines in vitro. We prepared mRQ micelles capable of retaining 1.1mg/mL and 1.42 mg/mL of RES and QUE respectively. The in vitro release of RES and QUE from the micelles followed first order kinetics over 48h. In vitro cell viability and combination index analysis studies in human ovarian cancer cells (SKOV-3) and rat cardiomyocytes (H9C2) showed that RES:QUE: ADR at 10:10:1 ratio was synergistic in SKOV-3 cells and antagonistic in H9C2 cells. Caspase 3/7 activity studies indicated that mRQ did not interfere with ADR caspase activity in SKOV-3 cells but significantly decreased it in H9C2 cells. The generation of reactive oxygen species (ROS) in SKOV-3 and H9C2 cells in the presence of mRQ also indicated no changes in ROS activity in SKOV-3 cells but significant scavenging in H9C2 cells. Healthy mice were exposed to acute doses of ADR and ADR with mRQ. Based on biochemical estimations the presence of mRQ with ADR conferred full cardioprotection in these mice. Concurrent administration of mRQ with ADR at 10:10:1 ratio provides a viable strategy to mitigate acute ADR induced cardiotoxicity.

Solid State Stability of Extemporaneously Prepared Levothyroxine Aliquots and Capsules.

The purpose of this research was to collect, analyze, and compare stability data for levothyroxine (T4) powder in the anhydrous and pentahydrate form when prepared as an aliquot and in capsules. Two different compounding pharmacies, Central Iowa Compounding and Gateway Medical Pharmacy, used different forms of T4 and aliquot formulations, which were studied to determine the beyond-use date at ±5% or ±10% of labeled strength. T4 was extracted from aliquot and capsule formulations and assessed using reverse-phase high- performance liquid chromatography validated to differentiate between the degraded and original forms of T4. The results indicate that T4 1:100 aliquot formulation prepared with silica gel or Avicel as filler are stable for 120 days at ±10% labeled potency, but at ±5% labeled potency, the silica gel and Avicel aliquot formulations are stable for 45 and 30 days, respectively. The silica gel capsules prepared from fresh aliquot were stable for 120 days at ±10% labeled potency and 90 days at ±5% labeled potency, while the Avicel capsules prepared from fresh aliquot were stable for 180 days at both ±10% and ±5% labeled potency. Avicel capsules prepared from old aliquot (120 days) and fresh aliquot (1 day) were also compared for stability. The old aliquot Avicel capsules were stable for 14 days at ±5% labeled potency and 150 days at ±10% labeled potency, while new aliquot Avicel capsules were stable for 180 days at both ±10% and ±5% labeled potency. Based on our data, there can be significant variation in the beyond-use dates assigned to T4 capsules based on the diluents used for aliquots, the final capsule formulations, and the potency standards applied. These results also indicate that pharmacists must exercise caution when using older aliquots and may have to assign shorter beyond-use dates.

Polymeric micellar co-delivery of resveratrol and curcumin to mitigate in vitro doxorubicin-induced cardiotoxicity.

Resveratrol (RES) and curcumin (CUR) have free radical scavenging ability and potential chemosensitizing effects. Doxorubicin hydrochloride (DH) is a potent chemotherapeutic with severe cardiotoxicity. We hypothesize that RES and CUR co-loaded in Pluronic(®) micelles and co-administered with DH will result in cardioprotective effects while maintaining/improving DH anti-proliferative effect in vitro. RES-CUR at a molar ratio of 5:1 in F127 micelles (mRC) were prepared and characterized for size, drug loading, and release. In vitro cell viability and apoptosis assays in ovarian cancer cells (SKOV-3) and cardiomyocytes (H9C2) with either individual drugs or RES-CUR or mRC in combination with DH were conducted. Combination index (CI) analysis was performed to determine combination effects. Reactive oxygen species (ROS) were quantified in H9C2 for DH, and combinations. The mRC solubilized 2.96 and 0.97 mg/mL of RES and CUR, respectively. Cell viability and CI studies indicated that the combinations were synergistic in SKOV-3 and antagonistic in H9C2 cells. Caspase 3/7 activity in combination treatments was lower than with DH alone in both cell lines. ROS activity was restored to baseline in H9C2 cells in the micelle combination groups. Co-administration of mRC with DH in vitro mitigates DH-induced cardiotoxicity through reduction in apoptosis and ROS while improving DH potency in ovarian cancer cells.