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In this study, we have formulated redox-responsive epidermal growth factor receptor (EGFR)-targeted type B gelatin nanoparticles as a targeted vector for systemic delivery of gemcitabine therapy in pancreatic cancer. The gelatin nanoparticles were formed by ethanol-induced desolvation process to encapsulate the bound drug. The surface of the nanoparticles was decorated either with poly(ethylene glycol) (PEG) chains to impart enhanced circulation time or with EGFR targeting peptide to confer target specificity. Our in vitro studies in Panc-1 human pancreatic ductal adenocarcinoma cells confirm that gemcitabine encapsulated in EGFR-targeted gelatin nanoparticles, released through disulfide bond cleavage, had a significantly improved cytotoxic profile. Further, the in vivo anticancer activity was evaluated in an orthotopic pancreatic adenocarcinoma tumor bearing SCID beige mice, which confirmed that EGFR-targeted gelatin nanoparticles could efficiently deliver gemcitabine to the tumor leading to higher therapeutic benefit as compared to the drug in solution. From the Clinical Editor The treatment of pancreatic cancer remains unsatisfactory, with an average 5-year survival of less than 5%. New treatment modalities are thus urgently needed. In this study, the authors presented their formulation of redox-responsive epidermal growth factor receptor (EGFR)-targeted type B gelatin nanoparticles as a carrier for gemcitabine. In-vitro and in-vivo experiments showed encouraging results. It is hoped that the findings would provide a novel and alternative drug delivery platform for the future.

It is clear that exosomes (endosome derived vesicles) serve important roles in cellular communication both locally and distally and that the exosomal process is abnormal in cancer. Cancer cells are not malicious cells; they are cells that represent 'survival of the fittest' at its finest. All of the mutations, abnormalities, and phenomenal adaptations to a hostile microenvironment, such as hypoxia and nutrient depletion, represent the astute ability of cancer cells to adapt to their environment and to intracellular changes to achieve a single goal - survival. The aberrant exosomal process in cancer represents yet another adaptation that promotes survival of cancer. Cancer cells can secrete more exosomes than healthy cells, but more importantly, the content of cancer cells is distinct. An illustrative distinction is that exosomes derived from cancer cells contain more microRNA than healthy cells and unlike exosomes released from healthy cells, this microRNA can be associated with the RNA-induced silencing complex (RISC) which is required for processing mature and biologically active microRNA. Cancer derived exosomes have the ability to transfer metastatic potential to a recipient cell and cancer exosomes function in the physical process of invasion. In this review we conceptualize the aberrant exosomal process (formation, content selection, loading, trafficking, and release) in cancer as being partially attributed to cancer specific differences in the endocytotic process of receptor recycling/degradation and plasma membrane remodeling and the function of the endosome as a signaling entity. We discuss this concept and, to advance comprehension of exosomal function in cancer as mediators of communication, we detail and discuss exosome biology, formation, and communication in health and cancer; exosomal content in cancer; exosomal biomarkers in cancer; exosome mediated communication in cancer metastasis, drug resistance, and interfacing with the immune system; and discuss the therapeutic manipulation of exosomal content for cancer treatment including current clinical trials of exosomal therapeutics. Often referred to as cellular nanoparticles, understanding exosomes, and how cancer cells use these cellular nanoparticles in communication is at the cutting edge frontier of advancing cancer biology.

Cell secreted exosomes (30-100nm vesicles) play a major role in intercellular communication due to their ability to transfer proteins and nucleic acids from one cell to another. Depending on the originating cell type and the cargo, exosomes can have immunosuppressive or immunostimulatory effects, which have potential application as immunotherapies for cancer and autoimmune diseases. Cellular components shed from tumor cells or antigen presenting cells (APCs), such as dendritic cells, macrophages and B cells, have been shown to be efficiently packaged in exosomes. In this review, we focus on the application of exosomes as nanocarriers and immunological agents for cancer and autoimmune immunotherapy. APC-derived exosomes demonstrate effective therapeutic efficacy for the treatment of cancer and experimental autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. In addition to their intrinsic immunomodulating activity, exosomes have many advantages over conventional nanocarriers for drug and gene delivery.

The purpose of the study was to evaluate the metabolism, pharmacokinetics and efficacy of phospho-NSAIDs in Ces1c-knockout mice.Hydrolysis of phospho-NSAIDs by Ces1c was investigated using Ces1c-overexpressing cells. The rate of phospho-NSAID hydrolysis was compared between wild-type, Ces1c+/- and Ces1c-/- mouse plasma in vitro, and the effect of plasma Ces1c on the cytotoxicity of phospho-NSAIDs was evaluated. Pharmacokinetics of phospho-sulindac was examined in wild-type and Ces1c-/- mice. The impact of Ces1c on the efficacy of phospho-sulindac was investigated using lung and pancreatic cancer models in vivo.Phospho-NSAIDs were extensively hydrolyzed in Ces1c-overexpressing cells. Phospho-NSAID hydrolysis in wild-type mouse plasma was 6-530-fold higher than that in the plasma of Ces1c-/- mice. Ces1c-expressing wild-type mouse serum attenuated the in vitro cytotoxicity of phospho-NSAIDs towards cancer cells. Pharmacokinetic studies of phospho-sulindac using wild-type and Ces1c-/- mice demonstrated 2-fold less inactivation of phospho-sulindac in the latter. Phospho-sulindac was 2-fold more efficacious in inhibiting the growth of lung and pancreatic carcinoma in Ces1c -/- mice, as compared to wild-type mice.Our results indicate that intact phospho-NSAIDs are the pharmacologically active entities and phospho-NSAIDs are expected to be more efficacious in humans than in rodents due to their differential expression of carboxylesterases.

New agents are needed to treat pancreatic cancer, one of the most lethal human malignancies. We synthesized phospho-valproic acid, a novel valproic acid derivative, (P-V; MDC-1112) and evaluated its efficacy in the control of pancreatic cancer. P-V inhibited the growth of human pancreatic cancer xenografts in mice by 60%–97%, and 100% when combined with cimetidine. The dominant molecular target of P-V was STAT3. P-V inhibited the phosphorylation of JAK2 and Src, and the Hsp90-STAT3 association, suppressing the activating phosphorylation of STAT3, which in turn reduced the expression of STAT3-dependent proteins Bcl-xL, Mcl-1 and survivin. P-V also reduced STAT3 levels in the mitochondria by preventing its translocation from the cytosol, and enhanced the mitochondrial levels of reactive oxygen species, which triggered apoptosis. Inhibition of mitochondrial STAT3 by P-V was required for its anticancer effect; mitochondrial STAT3 overexpression rescued animals from the tumor growth inhibition by P-V. Our results indicate that P-V is a promising candidate drug against pancreatic cancer and establish mitochondrial STAT3 as its key molecular target.

Phospho-sulindac (PS) is a safe sulindac derivative with promising anticancer efficacy in colon cancer. We evaluated whether its combination with curcumin could enhance the efficacy in the treatment of lung cancer. Curcumin, the principal bioactive component in turmeric, has demonstrated versatile capabilities to modify the therapeutic efficacy of a wide range of anticancer agents. Here, we evaluated the effect of co-administration of curcumin on the anticancer activity of PS in a mouse xenograft model of human lung cancer. Curcumin enhanced the cellular uptake of PS in human lung and colon cancer cell lines. To assess the potential synergism between curcumin and PS in vivo, curcumin was suspended in 10% Tween-80 or formulated in micellar nanoparticles and given to mice by oral gavage prior to the administration of PS. Both formulations of curcumin significantly improved the pharmacokinetic profiles of PS, with the 10% Tween-80 suspension being much more effective than the nanoparticle formation. However, curcumin did not exhibit any significant modification of the metabolite profile of PS. Furthermore, in a mouse subcutaneous xenograft model of human lung cancer, PS (200 mg/kg) in combination with curcumin (500 mg/kg) suspended in 10% Tween-80 (51% inhibition, p

Formulate phospho-sulindac (P-S, OXT-328) in a Pluronic hydrogel to be used as a topical anti-inflammatory agent and study its efficacy, safety and pharmacokinetics in an arthritis model.LEW/crlBR rats with Freund's adjuvant-induced arthritis were treated with P-S formulated in Pluronic hydrogel (PSH). We determined the clinical manifestations of arthritis including the locomotor activity of the rats; evaluated joints for inflammation, bone resorption, cartilage damage, COX-2 expression and NF-κB activation; assayed plasma IL-6 and IL-10 levels; and studied the pharmacokinetics of P-S in rats after topical or oral administration.PSH applied at the onset of arthritis or when arthritis was fully developed, suppressed it by 56-82%, improved the locomotor activity of the rats 2.1-4.4 fold, suppressed synovial inflammation, bone resorption, cartilage damage, NF-κB activation and COX-2 expression but not plasma IL-6 and IL-10 levels. There were no side effects. PSH produced rapidly high local levels of P-S with14% of P-S reaching the circulation, while orally administered P-S was rapidly metabolized generating much lower joint levels of P-S.Topical application of PSH is efficacious and safe in the treatment of Freund's adjuvant-induced arthritis; has a favorable pharmacokinetic profile; and likely acts by suppressing key pro-inflammatory signaling pathways.

To develop scleral controlled-release-systems of triamcinolone acetonide (TA) based on biodegradable poly(lactide) (PLA).(1) PLA microspheres containing TA were prepared by a single or double emulsification-solvent evaporation method. Morphology, size, effect of drug input and method of microsphere preparation on drug loading, and in vitro TA release of the microspheres were investigated. (2) Mini-tablets consisting of blank PLA-microspheres and TA (weight ratios of 1:1, 2:1, and 4:1, respectively) were developed and their release profile in vitro was evaluated. (3) The in vitro transscleral diffusion profile was evaluated by placing a PLA-TA (1:1) tablet in a donor chamber and measuring the TA concentration in a receptor chamber. Donor and receptor chambers were separated by rabbit sclera. (4) Two cadaver rabbit eyes received a 1:1 PLA-TA tablet episclerally, which was covered by a scleral patch. TA aqueous humor and vitreous concentrations were measured 5, 10, and 20 days post implantation.(1) Microsphere average size was 2 μm. The double emulsification method and increasing drug input led to an increase in drug loading and encapsulation. Sustained release of TA over several days from the microspheres in vitro was observed, with the rate of release being affected by their TA content. (2) TA exhibited sustained release profile from the PLA-TA tablets, with the rate of release being affected by the PLA:TA ratio. (3) TA could slowly cross the sclera tissue in vitro, with approximately 21% of the drug loaded in the donor compartment being diffused through the sclera in 45 days. (4) Following scleral administration of the PLA-TA mini-tablets, TA accumulated in the vitreous and aqueous humor of cadaver eyes.The PLA-TA microspheres and mini-tablets appear promising for the controlled transscleral delivery of TA and justify further investigation.

Hybrid nanocolloids based on biodegradable polymers of poly(lactide) (PLA) or poly(lactide)-block-poly(ethylene glycol) (PLA-PEG) and hydrophobic iron oxide magnetic nanoparticles (MNPs) of ca. 5 nm are prepared via a self-assembly route. The magnetic nanoparticles are organized in superclusters inside the hydrophobic core of PLA-PEG micelles or cholate-stabilized PLA nanospheres. The hydrodynamic diameter of MNPs-loaded PLA nanospheres is approximately 250 nm, whereas that of MNPs-loaded PLA-PEG micelles is much lower (approximately 100 nm) and thus compatible with applications where prolonged blood circulation is required. The PLA-PEG micelles exhibit high encapsulation efficiency for the MNPs, imparting a saturation magnetization value to the hybrid of 8.4 emu g(-1). Both hybrid colloids display magnetic properties of a non-interacting assembly of superparamagnetic particles and a low blocking temperature, both of which are key attributes for colloidally stable ferrofluids. Furthermore, the PLA-PEG magnetic hybrids display remarkable colloidal stability at high ionic strength, temperature and in human blood plasma, while the estimated critical micelle concentration of ca. 2 x 10(-5) mM (0.3 mg L(-1)) indicates the low probability of the colloids dissociation in the blood compartment. They were also found to be non-toxic to human cells in vitro. The results underline the potential of the magnetic/PLA-PEG hybrids and encourage further research for their in vivo biomedical applications.

Novel amphiphilic triblock copolymers of poly(propylene succinate) (PPSu) and poly(ethylene glycol) (PEG) with different hydrophobic/hydrophilic ratios were synthesized using a facile one-pot procedure. The molecular weight of the copolymers was adjusted by varying the molecular weight of PPSu while keeping that of PEG constant. The copolymers exhibited glass transition temperatures between -36.0 and -38°C and single melting points around 44°C. WAXD data indicated that both blocks of the copolymers could crystallize. The mPEG-PPSu copolymers exhibited low in vitro toxicity against HUVEC cells. The synthesized copolymers were used to prepare core-shell nanoparticles with hydrophobic PPSu and hydrophilic PEG forming the core and shell, respectively. The drug loading efficiency and drug release properties of the mPEG-PPSu nanoparticles were investigated using two model drugs: the hydrophilic Ropinirole and the hydrophobic Tibolone. The mean size of the drug-loaded mPEG-PPSu nanoparticles ranged between 150 and 300nm and increased with the molecular weight of the PPSu block. The drug loading efficiency of the nanoparticles was found to be dependent upon drug hydrophilicity and was much higher for the hydrophobic Tibolone. Drug release characteristics also depended on drug hydrophilicity: the hydrophilic Ropinirole was released at a much higher rate than the hydrophobic Tibolone. Contrary to Ropinirole, the profiles of Tibolone exhibited an early phase of burst release followed by a phase of slow release. By varying the composition (mPEG/PPSu ratio) of mPEG-PPSU copolymers, nanoparticles of different sizes and drug loading capacities can be synthesized exhibiting different drug release characteristics. Based on the results obtained, the proposed mPEG-PPSu copolymers can be useful in various controlled drug delivery applications, especially those involving relatively hydrophobic drugs.

We investigated the behavior of the pH and thermo-responsive poly(2-(diethylamino)ethyl methacrylate-co-methacrylic acid)-b-(ethylene glycol methyl ether methacrylate)-b-poly(2-(diethylamino)ethyl methacrylate-co-methacrylic acid) (P(DEAEMA-co-MAA)-b-PEGMA-b-P(DEAEMA-co-MAA)) triblock terpolymers in aqueous solution by means of static and dynamic light scattering, transmission electron microscopy and rheology. Association phenomena were observed at the isoelectric point region of the polyampholyte outer blocks leading to flower-like micelles and at higher polymer concentrations, to a three dimensional transient micellar network, exhibiting a compex thermo-response thanks to the thermo-sensitivity of the PEGMA middle block. Doxorubicin (DOX) drug was loaded in the terpolymer micelles and drug release studies were performed. Controlled drug delivery could be achieved by tuning pH. The terpolymer micelles exhibited satisfactory cytocompatibility towards human umbilical vein endothelial cells.