Dual Conjugate Research Articles

A hyaluronic acid conjugate engineered to synergistically and sequentially deliver gemcitabine and doxorubicin to treat triple negative breast cancer

Combination chemotherapy is commonly used to treat advanced breast cancer. However, treatment success is often limited due to systemic toxicity. To improve therapeutic efficacy, polymer drug conjugates carrying synergistic pairs of chemotherapy drugs can be used to reduce drug administration dose. Here, we systematically evaluated the effect of temporal scheduling of doxorubicin (DOX) and gemcitabine (GEM) on drug synergy. Hyaluronic acid (HA) drug conjugates with distinct linkers conjugating both DOX and GEM were synthesized to control relative release kinetics of each drug. We show that polymer conjugates that release GEM faster than DOX are more effective at killing triple negative breast cancer cells in vitro. We further show that the optimal dual drug conjugate more effectively inhibits the growth of an aggressive, orthotopic 4T1 tumor model in vivo than free DOX and GEM and the single drug HA conjugates. The dual drug HA conjugate can inhibit 4T1 tumor growth in vivo during treatment through both intravenous and non-local subcutaneous injections. These results emphasize the importance of understanding the effect release rates have on the efficacy of synergistic drug carriers and motivate the use of HA as a delivery platform for multiple cancer types.

A VAR2CSA:CSP conjugate capable of inducing dual specificity antibody responses.

Vaccine antigens targeting specific P. falciparum parasite stages are under pre-clinical and clinical development. It seems plausible that vaccine with multiple specificities will offer higher protection. With this hypothesis, we exploited the Spy-Tag/SpyCatcher conjugation system to make a, post expression, dual antigen conjugate vaccine, comprising two clinically tested antigen candidates (CSP and VAR2CSA). The DBL1x-DBL2x-ID2a region of VAR2CSA was genetically fused with SpyTag at N-terminus. The full-length CSP antigen was genetically fused to C-terminal SpyCatcher peptide. The covalent interaction between SpyTag/SpyCatcher enables the formation of DBL1x-DBL2x-ID2a:CSP conjugate vaccine. Immunogenicity and quality of antibody responses induced by the conjugate vaccine, as well as a control CSP-SpyCatcher vaccine, was tested in BALB/c mice. Serum samples obtained from mice immunized with the conjugate vaccine were able to recognize both untagged DBL1x-DBL2x-ID2a as well as CSP antigen. Moreover, the geometric mean anti-CSP antibody titer was 1.9-fold higher in serum (at day 35 and 55 post-first immunization) from mice immunized with the conjugate vaccine, as compared to mice receiving the control vaccine. The data obtained in this study serves as proof-of-concept for the simultaneous induction of antibodies directed against individual antigen components in a dual stage anti-malaria vaccine.

A dual functional peptide-auxiliary conjugate for C-to-N and N-to-C sequential native chemical ligation of glycopeptides

Long, homogeneously glycosylated peptides and proteins can be assembled from multiple segments via sequential chemoselective reactions. The efficiency of the synthesis depends on the effectiveness and number of steps and on their compatibility with glycosylation methods. Here, we present how the combination of auxiliary-mediated native chemical ligation and thioester generation via hydrazinolysis from Wang-type resin enables multiple, sequential N-to-C and C-to-N ligations. The method can be applied to glycosylated peptides and peptide α-thioesters and has the potential to be further extended to sequential glycosylation, thus paving the way to the synthesis of complex homogeneous glycoproteins. We applied this methodology to the synthesis of long MUC1 variants comprising 2, 4 and 6 tandem repeats and three O-glycosylations.

Reversion of P-gp-Mediated Drug Resistance in Ovarian Carcinoma Cells with PHPMA-Zosuquidar Conjugates.

Inhibition of P-glycoprotein (P-gp) transporter is an attractive approach for the reversion of cancer-associated multidrug resistance (MDR). Poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA)-based carriers that are able to release the anticancer drug doxorubicin in the lysosomes have shown promise to reduce P-gp mediated resistance. This is attributed to the release of the drug in close proximity to the nucleus and distant from the P-gp transporter. This work presents a strategy to maximize P-gp inhibition and enhance doxorubicin cytotoxicity in cancer cells by using a dual functional PHPMA conjugate carrying both the anticancer drug doxorubicin and the P-glycoprotein inhibitor zosuquidar (Zos). While doxorubicin was connected to the polymer backbone via a lysosomally cleavable spacer, the P-gp inhibitor Zos was attached by a hydrazone linker in order to promote release in the early stage of the endocytic process and maximize its cytosolic concentration in proximity of the P-gp transporter. Following Zos modification and determination of its ability to inhibit P-gp, conjugation to the PHPMA polymer backbone resulted in enhanced doxorubicin cytotoxicity in resistant A2780ADR ovarian carcinoma cells. Finally, the incorporation of both Dox and Zos in a single polymer carrier enhanced P-gp inhibition as compared to a control PHPMA conjugate containing only Dox.

Novel dual VES phospholipid self-assembled liposomes with an extremely high drug loading efficiency

Vitamin E succinate (VES), a unique selective anti-cancer drug, has attracted much attention for its ability to induce apoptosis in various cancer cells. Importantly, it has been reported that VES is largely non-toxic to normal cells. However, poor aqueous solubility and bioavailability extensively restricted its clinical utility. In this report, dual VES phospholipid conjugate (di-VES-GPC) prodrug based liposomes were prepared in order to develop an efficient delivery system for VES. Di-VES-GPC was first synthesized by conjugating VES with l-α-glycerophosphorylcholine (GPC) using N,N′-dicyclohexylcarbodiimide (DCC) as a coupling agent. The di-VES-GPC prodrug was able to self-assemble into liposomes by reverse-phase evaporation method. The structure of the liposomes was characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM) and cryo-TEM. The results showed that di-VES-GPC assembled liposomes were spherical with an average diameter approximately 183nm. Cryo-TEM data confirmed the formation of multilamellar liposomes with the bilayer thickness about 5nm by the assembly of the conjugate without any excipient. The VES drug loading highly reaches up to 82.8wt% in the liposomes after a simple calculation. Furthermore, the in vitro release behavior of di-VES-GPC liposomes was evaluated in different media. It was found that the liposomes could release free VES at a weakly acidic microenvironment but exhibited good stability under a simulated biological condition. The cellular uptake and intracellular drug release tests demonstrated that di-VES-GPC liposomes could be internalized effectively and converted into parent drug VES in cancer cells. Furthermore, in vitro antitumor activities of the di-VES-GPC liposomes were evaluated by MTT assay and flow cytometry. It was revealed that the liposomes presented comparable cytotoxicities to free VES. Taken together, the di-VES-GPC liposomes might provide an excellent formulation of VES which have potential in the treatment of cancers.

Dual 7-ethyl-10-hydroxycamptothecin conjugated phospholipid prodrug assembled liposomes with in vitro anticancer effects

7-Ethyl-10-hydroxycamptothecin (SN38), as a highly active topoisomerase I inhibitor, is 200–2000-fold more cytotoxic than irinotecan (CPT-11) commercially available as Camptosar®. However, poor solubility and low stability extensively restricted its clinical utility. In this report, dual SN38 phospholipid conjugate (Di-SN38-PC) prodrug based liposomes were developed in order to compact these drawbacks. Di-SN38-PC prodrug was first synthesized by inhomogeneous conjugation of two SN38-20-O-succinic acid molecules with L-α-glycerophosphorylcholine (GPC). The assembly of the prodrug was carried out without any excipient by using thin film method. Dynamic light scattering (DLS), transmission electron microscope (TEM) and cryogenic transmission electron microscopy (cyro-TEM) characterization indicated that Di-SN38-PC can form spherical liposomes with narrow particle size (<200nm) and negatively charged surface (-21.6±3.5mV). The loading efficiency of SN38 is 65.2 wt.% after a simple calculation. In vitro release test was further performed in detail. The results demonstrated that Di-SN38-PC liposomes were stable in neutral environment but degraded in a weakly acidic condition thereby released parent drug SN38 effectively. Cellular uptake studies reflected that the liposomes could be internalized into cells more significantly than SN38. In vitro antitumor activities were finally evaluated by MTT assay, colony formation assay, flow cytometry, RT-PCR analysis and Western Blot. The results showed that Di-SN38-PC liposomes had a comparable cytotoxicity with SN38 against MCF-7 and HBL-100, and a selective promotion of apoptosis of tumor cells. Furthermore, a pharmacokinetics test showed that Di-SN38-PC liposomes had a longer circulating time in blood compared with the parent drug. All the results indicate that Di-SN38-PC liposomes are an effective delivery system of SN38.

Realization and Extension of Data Hiding Methods in Gray-scale Halftone Images

This paper realizes and extends data hiding methods in gray-scale halftone images. Firstly, this paper reviews previous methods of data hiding in gray-scale halftone images. Secondly, this paper realizes and extends these methods. Finally, this paper compares the performance of different methods. According to the experimental results, it can be summarized: the CDRs using dual conjugate property are better than single conjugate property; using Jarvis kernel the reveal pattern has better CDRs than using Floyd-Steinberg kernel; Jarvis kernel the reveal pattern has better CDRs than in dot diffusion halftone images; for gray-scale halftone images, and DHDCED is the best method of previous methods.

Nanoformulation of dual bexarotene-tailed phospholipid conjugate with high drug loading

Bexarotene (Bex), a synthetic retinoid X receptor-selective activator, has been proved to be an efficacious chemotherapeutic agent. But, its clinical application is limited due to the poor solubility. In this report, dual bexarotene-tailed phospholipid (DBTP) conjugate based nanovesicles were prepared in order to develop new nanoformulation. DBTP conjugate was first synthesized by conjugating two Bex molecules with glycerophosphorylcholine (GPC) through facial esterification. The amphiphilic DBTP nanovesicles were prepared without any additive by reverse-phase evaporation method. They were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The results revealed that the DBTP nanovesicles have a spherical structure with an average diameter approximately 138.7nm and a negatively charged surface (−33.3±2.5mV). The loading efficiency of Bex is 76wt% after a simple calculation. In vitro degradation of DBTP nanovesicles and the release of Bex were further studied in detail. The results demonstrated that DBTP nanovesicles were stable in neutral environment but degraded in a weakly acidic condition and released parent drug Bex effectively. Cellular uptake was investigated by confocal laser scanning microscope (CLSM) and liquid chromatography-mass spectroscopy (LC-MS). The results demonstrated the successful internalization and intracellular release of DBTP nanovesicles. Furthermore, the cytotoxicity analysis and apoptosis of the nanovesicles showed higher antitumor activities compared with free Bex. In a conclusion, DBTP nanovesicles could be an effective nanoformulation of Bex.

STRICT CONVEXITY THROUGH EQUIVALENT NORMS IN SEPARABLES BANACH SPACES

Let E be a separable Banach space with norm || . ||. In the present work, the objective is to construct a norm || . ||1 that is equivalent to || . || in E, such that || . ||1 is strictly convex. In addition it is shown that its dual conjugate norm is also strictly convex.

Development and Optimization of Dual Drugs (Isoniazid and Moxiflox-acin) Loaded Functional PLGA Nanoparticles for the Synergistic Treatment of Tuberculosis.

The management of TB is difficult due to the resistance developed by Mycobacterium tuberculosis against anti-tubercular drugs causes the new challenges for treating and managing the disease. The objective of the study was to combat multiple drug resistance (MDR) exhibited by mycobacterium species by synthesizing Dual Drug Conjugate nanoparticle (DDC) using Isoniazid (INH) and Moxifloxacin (MOXI). The reaction was nucleophilic substitution using hydrolysable linkers like Chloroacetyl chloride (CAC) & Succinyl chloride (SCL). The drugs were covalently linked as INH-CAC-MOXI (DDC-1) and INH-SCL-MOXI (DDC-2). The DDC-1 & DDC-2 were subjected to hydrolysability tests at different pH solutions. The modified drugs were formulated into Poly (D, L-Lactic-co-Glycolide) nanoparticles using single emulsion technique. Design Expert® (version 8.0.1) software was used for designing, and evaluating the prepared formulation by employing response surface, optimal design of experiment technique. The prepared nanoparticles were characterized for compatibility studies using Fourier Transform Infrared Spectroscopy, Nuclear Magnetic Resonance, particle size, size distribution, Zeta potential, drug entrapment efficiency and Scanning Electron Microscopy. Microbiological studies on pure drug and the conjugate indicated better activity of conjugate compared to pure drug alone or 1:1 physical mixture of drug. The nanoparticles were further subjected to drug release studies and accelerated stability studies. The present study offers a key to the challenge of loading different types of drugs onto the same drug delivery vehicle with efficient loading capacity, thus enabling better treatment for TB.

Dual Targeting of Intracellular Pathogenic Bacteria with a Cleavable Conjugate of Kanamycin and an Antibacterial Cell-Penetrating Peptide.

Bacterial infection caused by intracellular pathogens, such as Mycobacterium, Salmonella, and Brucella, is a burgeoning global health epidemic that necessitates urgent action. However, the therapeutic value of a number of antibiotics, including aminoglycosides, against intracellular pathogenic bacteria is compromised due to their inability to traverse eukaryotic membranes. For this significant problem to be addressed, a cleavable conjugate of the antibiotic kanamycin and a nonmembrane lytic, broad-spectrum antimicrobial peptide with efficient mammalian cell penetration, P14LRR, was prepared. This approach allows kanamycin to enter mammalian cells as a conjugate linked via a tether that breaks down in the reducing environment within cells. Potent antimicrobial activity of the P14KanS conjugate was demonstrated in vitro, and this reducible conjugate effectively cleared intracellular pathogenic bacteria within macrophages more potently than that of a conjugate lacking the disulfide moiety. Notably, successful clearance of Mycobacterium tuberculosis within macrophages was observed with the dual antibiotic conjugate, and Salmonella levels were significantly reduced in an in vivo Caenorhabditis elegans model.

Halftone image watermarking via optimization

Although halftone image watermarking technologies have been rapidly developing in the 21st century, the existing techniques lack a theoretical basis. In this paper, we tackle halftone image watermarking problems from a theoretical perspective. First, we propose a general optimization framework for Halftone Visual Watermarking (HVW), which is a certain category of halftone image watermarking techniques. Then two specific HVW problems, Single-sided Embedding Error Diffusion (SEED) and Double-sided Embedding Error Diffusion (DEED) are presented and solved by applying the proposed framework. With SEED and DEED obtained, both the theoretical solutions and experimental results indicate that our previous heuristic methods, Data Hiding by Conjugate Error Diffusion (DHCED) and Data Hiding by Dual Conjugate Error Diffusion (DHDCED), are special cases of SEED and DEED, respectively. We also demonstrate that DEED can achieve outstanding performance compared to DHDCED and other previous methods by selecting different parameters. With this paper, we essentially build a bridge between the theory and practical implementations of HVW problems.

Liposome-like nanocapsules of dual drug-tailed betaine for cancer therapy

A novel dual drug-tailed betaine conjugate amphiphile has been firstly synthesized in which the polar headgroup is derived from glycine betaine and the hydrophobic tails are chlorambucil molecules. The newly prepared conjugate undergoes self-assembly to form stable liposome-like nanocapsules as an effective carrier with high drug loading capacity. The nanocapsules showed higher cytotoxic effects to cancer cell lines than those of free chlorambucil in vitro, and inhibited tumor growth effectively in vivo. This strategy that utilizes new dual drug-tailed betaine conjugate amphiphile to construct a self-assembled nanoparticle drug delivery system may have great potential in cancer chemotherapy.

Abstract 1680: In vitro and in vivo activity of a highly potent and novel FGFR2/FGFR4 dual targeting antibody-drug conjugate

Abstract The fibroblast growth receptors 2 and 4 (FGFR2, FGFR4) are overexpressed in a broad spectrum of malignancies. In a subset of breast, gastric, and esophageal cancers, increased FGFR2 expression is driven by FGFR2 copy number (CN) gain, which renders these tumors dependent on FGFR2 pathway activation and is associated with poor prognosis. FGFR4 expression is increased in response to both FGFR4 CN gain, as seen in embryonal rhabdomyosarcoma, or by the PAX3-FOXO1 fusion gene product which transcriptionally activates FGFR4, as seen in alveolar rhabdomyosarcoma. Additionally, other mechanisms drive increased FGFR2 expression, e.g. in subsets of lung and breast cancer, and increased FGFR4 expression, e.g. in subsets of hepatocellular, breast, and pancreatic cancer. This elevated expression in malignancies combined with the observation that FGFR2 and FGFR4 are efficiently internalized upon antibody binding make both receptors attractive targets for antibody-drug conjugate (ADC) therapy. To this end, a drug discovery campaign was initiated and a novel, highly potent FGFR2, FGFR4 dual targeting ADC was discovered. This ADC consists of a fully human antibody (discovered in collaboration with MorphoSys) conjugated to the potent maytansine-derived microtubule-disruptor, DM1, via an SMCC non-cleavable thioether linkage (linker payload technology licensed from ImmunoGen, Inc.). In vitro, the ADC is active against FGFR2 and FGFR4 positive cells in viability assays and is efficiently processed yielding the principle catabolite Lys-SMCC-DM1. In vivo, the ADC is highly efficacious against a variety of disease relevant xenograft models including FGFR2 amplified breast and gastric models and a PAX3-FOXO1 translocation positive alveolar rhabdomyosarcoma model. Additionally, the ADC is potent against a subset of primary tumor derived breast and lung xenograft models that lack FGFR2 CN gain or the PAX3-FOX01 translocation. Consistent with the molecule's mode of action, anti-tumor activity is preceded by G2/M cell cycle arrest and apoptosis. Taken together these data suggest that this novel, dual targeting ADC may be an effective treatment for patients with FGFR2 or FGFR4 positive tumors including, but not limited to those with FGFR2 CN gain or the PAX3-FOXO1 fusion gene. Citation Format: Matthew J. Meyer, David Jenkins, David Batt, Rebecca Mosher, Randi Isaacs, Tiancen Hu, Vladimir Capka, Xiamei Zhang, Dongshu Chen, Lujia Tang, Mike Daley, Patrycja Nowakowski, Yeonju Shim, Wei Jiang, Seth Ettenberg, Emma Lees. In vitro and in vivo activity of a highly potent and novel FGFR2/FGFR4 dual targeting antibody-drug conjugate. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1680. doi:10.1158/1538-7445.AM2015-1680

Equiaffine structure and conjugate Ricci-symmetry of a statistical manifold

A condition for a statistical manifold to have an equiaffine structure is studied. The facts that dual flatness and conjugate symmetry of a statistical manifold are sufficient conditions for a statistical manifold to have an equiaffine structure were obtained in [4] and [5]. In this paper, a fact that a statistical manifold, which is conjugate Ricci-symmetric, has an equiaffine structure is given, where conjugate Ricci-symmetry is a weaker condition than conjugate symmetry. A condition for conjugate symmetry and conjugate Ricci-symmetry to coincide is also given.

Polymeric Nanomedicine for Tumor-Targeted Combination Therapy to Elicit Synergistic Genotoxicity against Prostate Cancer

To improve the therapeutic efficacy of anticancer combination therapy, we designed a nanoplatform based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers that allows covalent bonding of two chemotherapeutics acting via different anticancer mechanisms and that can enter target cells by receptor-mediated endocytosis. Doxorubicin (DOX) was covalently conjugated to a nanosized HPMA copolymer using a pH-sensitive hydrazone bond and 5-fluorouracil (5-Fu) was conjugated to the same backbone using an enzymatically degradable oligopeptide Gly-Phe-Leu-Gly sequence. Then, the conjugate was decorated with galectin-3 targeting peptide G3-C12 [P-(G3-C12)-DOX-Fu]. The two drugs showed similar in vitro release profiles, suggesting that they may be able to work synergistically in the codelivery system. In galectin-3 overexpressed PC-3 human prostate carcinoma cells, P-(G3-C12)-DOX-Fu surprisingly exhibited comparable cytotoxicity to free DOX at high concentration by increasing cell internalization and exerting synergistic genotoxic effects of cell cycle arrest, caspase-3 activation, and DNA damage. In mice bearing PC-3 tumor xenografts, the use of tumor-targeting ligand substantially enhanced the intracellular delivery of P-(G3-C12)-DOX-Fu in tumors. The targeted dual drug-loaded conjugate inhibited tumor growth to a greater extent (tumor inhibition of 81.6%) than did nontargeted P-DOX-Fu (71.2%), P-DOX (63%), DOX·HCl (40.5%), P-Fu (32.0%), or 5-Fu (14.6%), without inducing any obvious side effects. These results demonstrate the potential of synergistic combination therapy using targeted nanocarriers for efficient treatment of prostate cancer.

Exploring cancer metastasis prevention strategy: interrupting adhesion of cancer cells to vascular endothelia of potential metastatic tissues by antibody-coated nanomaterial.

BackgroundCancer metastasis caused by circulating tumor cells (CTCs) accounts for 90% cancer-related death worldwide. Blocking the circulation of CTCs in bloodstream and their hetero-adhesion to vascular endothelia of the distant metastatic organs may prevent cancer metastasis. Nanomaterial-based intervention with adhesion between CTCs and endothelia has not been reported. Driven by the novel idea that multivalent conjugation of EpCAM and Slex antibodies to dendrimer surface may enhance the capacity and specificity of the nanomaterial conjugates for capturing and down-regulating colorectal CTCs, we conjugated the dendrimer nanomaterial with the EpCAM and Slex antibodies, and examined the capacity of the dual antibody-coated nanomaterial for their roles in interrupting CTCs-related cancer metastasis.ResultsThe antibody-coated nanomaterial was synthesized and characterized. The conjugates specifically bound and captured colon cancer cells SW620. The conjugate inhibited the cells’ viability and their adhesion to fibronectin (Fn)-coated substrate or human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. In comparison with SW480 and LoVo cell lines, the activity and adhesion of SW620 to Fn-coated substrate and HUVECs were more specifically inhibited by the dual antibody conjugate because of the higher levels of EpCAM and Slex on SW620 cell surface. The hetero-adhesion between SW620 and Fn-coated substrate, or HUVECs was inhibited by about 60-70%. The dual conjugate showed the inhibition capacity more significant than its corresponding single antibody conjugates.ConclusionsThe present study provides the new evidence that coating nanomaterials with more than one antibody against CTCs may effectively interfere with the interaction between SW620 and HUVECs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-015-0072-x) contains supplementary material, which is available to authorized users.

Enhanced Specificity in Capturing and Restraining Circulating Tumor Cells with Dual Antibody–Dendrimer Conjugates

Specifically capturing and restraining residual circulating tumor cells (CTCs) in cancer patients are the sine qua non for safely and effectively preventing cancer metastasis, to which the current chemotherapy has been limited due to its toxicity. Moreover, because of CTCs’ rarity and low activity, the current technology for capturing CTCs based solely on a single surface biomarker has limited capacity and is used mainly for in vitro diagnosis. Here, it is possible to sequentially conjugate two CTCs antibodies (aEpCAM and aSlex) to the functionalized dendrimers to specifically capture human hepatocellular CTCs in both artificial and clinical patient blood samples, and restrain their activities. The molecular entities of the conjugates are demonstrated by various means. The dual antibody conjugate captured CTCs threefold more than the single counterparts from the high concentrations of interfering red blood cells or leukocytes, as well as from the blood of liver cancer patients, and exhibits the superiority to their single counterparts in down‐regulating the captured CTCs. These results collectively provide the strong evidence that two antibodies can be compatibly conjugated to a nanomaterial, resulting in an enhanced specificity in restraining CTCs in blood.

Modelling as The Development Instrument of Commodity and Financial Networks in Regional Economy

The article is devoted to investigations of the relationship of commodity-production and financial network structures in the regional economy as dual conjugate systems. Material flows (raw materials, goods, etc.) are circulating in the commodity network according to the Leontyev, input-output model. Nonmaterial flows of property rights, money, etc. in the financial network are reflecting the movement of material objects. Network structure is considered to be a complex of closed and open circuits that are carrying out two fundamentally different problems: a locally closed circuits are meeting local demands by supplying of locally produced goods that is providing self-reproduction of the local economy; open (or transit) circuits are providing export-import flows. The generation mechanism of «internal» money in closed circuits of commodity-production network is presented. Obtained theoretical results are illustrated by calculations of closed and open circuit flows in the municipality economy model. The mathematical model represents the mutual payments of population and companies in matrix form. It is found that the volume of turnover in closed circuits is about 28.5 % of total municipality economy model turnover and can be assured by «internal» non-inflationary money. The remaining 71.5 % of total turnover are corresponding to the flows in open circuits of the network providing export and import activity. It is summarized that the priority of innovative economy projects should be given to domestic consumption rather than exports.

Commodity and Financial Networks in Regional Economics

The article discusses the relationship between commodity-production and financial network structures in the regional economy as dual conjugate systems. Material flows (raw materials, goods and so on) circulate in the commodity network as shown by Leontiev’s input-output balance model. Nonmaterial flows of property rights, money, and so on circulate in the financial network and reflect the movement of material objects in commodity networks. A network structure comprises closed and open circuits, which have fundamentally different characteristics: locally closed circuits meet local demand by supplying locally produced goods, thus ensuring self-reproduction of the local economy; open (or transit) circuits provide export-import flows. The article describes the mechanism of ‘internal’ money generation in closed circuits of commodity-production networks. The results of the theoretical study are illustrated by the calculations of closed and open circuit flows in the municipal economy model. Mutual settlements between the population and manufacturing enterprises are given in matrix form. It was found that the volume of the turnover in closed circuits of the municipal economic network model is about 28.5 % of the total turnover and can be provided by ‘internal’ non-inflationary money. The remaining 71.5 % of the total turnover correspond to the flows in the network’s open circuits providing export and import. The conclusion is made that in the innovation-driven economy, main attention should be given to the projects oriented towards domestic consumption rather than export supplies. The economy is based on internal production cycles in closed circuits. Thus, it is necessary to find the chains in the inter-industrial and inter-production relations which could become the basis of the production cycle. Money investments will complete such commodity chains and ‘launch’ the production cycle.