79 results found
Chongchai A, Waramit S, Wongwichai T, et al., 2021, Targeting human osteoarthritic chondrocytes with ligand directed bacteriophage-based particles, Viruses, Vol: 13, ISSN: 1999-4915
Osteoarthritis (OA) is a degenerative joint disease characterized by progressive deterioration and loss of articular cartilage. There is currently no treatment to reverse the onset of OA. Thus, we developed a targeted delivery strategy to transfer genes into primary human chondrocytes as a proof-of-concept study. We displayed a chondrocyte-affinity peptide (CAP) on the pIII minor coat protein of the M13 filamentous bacteriophage (phage)-based particle carrying a mammalian transgene cassette under cytomegalovirus CMV promoter and inverted terminal repeats (ITRs) cis elements of adeno-associated virus serotype 2 (AAV-2). Primary human articular chondrocytes (HACs) were used as an in vitro model, and the selectivity and binding properties of the CAP ligand in relation to the pathogenic conditions of HACs were characterized. We found that the CAP ligand is highly selective toward pathogenic HACs. Furthermore, the stability, cytotoxicity, and gene delivery efficacy of the CAP-displaying phage (CAP.Phage) were evaluated. We found that the phage particle is stable under a wide range of temperatures and pH values, while showing no cytotoxicity to HACs. Importantly, the CAP.Phage particle, carrying a secreted luciferase (Lucia) reporter gene, efficiently and selectively delivered transgene expression to HACs. In summary, it was found that the CAP ligand preferably binds to pathogenic chondrocytes, and the CAP.Phage particle successfully targets and delivers transgene to HACs.
Vassileva V, Braga M, Barnes C, et al., 2021, Effective detection and monitoring of glioma using [18F]FPIA PET imaging, Biomedicines, Vol: 9, Pages: 1-14, ISSN: 2227-9059
Background: Reprogrammed cellular metabolism is a cancer hallmark. In addition to increased glycolysis, the oxidation of acetate in the citric acid cycle is another common metabolic phenotype. We have recently developed a novel fluorine-18-labelled trimethylacetate-based radiotracer, [18F]fluoro-pivalic acid ([18F]FPIA), for imaging the transcellular flux of short-chain fatty acids, and investigated whether this radiotracer can be used for the detection of glioma growth. Methods: We evaluated the potential of [18F]FPIA PET to monitor tumor growth in orthotopic patient-derived (HSJD-GBM-001) and cell line-derived (U87, LN229) glioma xenografts, and also included [18F]FDG PET for comparison. We assessed proliferation (Ki-67) and the expression of lipid metabolism and transport proteins (CPT1, SLC22A2, SLC22A5, SLC25A20) by immunohistochemistry, along with etomoxir treatment to provide insights into [18F]FPIA uptake. Results: Longitudinal PET imaging showed gradual increase in [18F]FPIA uptake in orthotopic glioma models with disease progression (p < 0.0001), and high tumor-to-brain contrast compared to [18F]FDG (p < 0.0001). [18F]FPIA uptake correlated positively with Ki-67 (p < 0.01), SLC22A5 (p < 0.001) and SLC25A20 (p = 0.001), and negatively with CPT1 (p < 0.01) and SLC22A2 (p < 0.01). Etomoxir reduced [18F]FPIA uptake, which correlated with decreased Ki-67 (p < 0.05). Conclusions: Our findings support the use of [18F]FPIA PET for the detection and longitudinal monitoring of glioma, showing a positive correlation with tumor proliferation, and suggest transcellular flux-mediated radiotracer uptake.
Chongchai A, Waramit S, Suwan K, et al., 2021, Bacteriophage‐mediated therapy of chondrosarcoma by selective delivery of the tumor necrosis factor alpha (TNFα) gene, The FASEB Journal, Vol: 35, ISSN: 0892-6638
Chondrosarcoma is a cartilage‐forming bone tumor, well known for intrinsic resistance to chemotherapy and radiotherapy. We have designed a targeted chondrosarcoma gene therapy using a bacteriophage (phage) particle to deliver therapeutic genes. Phage has no tropism for mammalian cells, allowing engineered phage to be targeted to specific cell surface receptors in cancer. We modified the phage capsid to display the RGD4C ligand on the pIII minor coat proteins to specifically bind to αvβ3 or αvβ5 integrin receptors. The endosomal escape peptide, H5WYG, was also displayed on recombinant pVIII major coat proteins to enhance gene delivery. Finally, a human tumor necrosis factor alpha (TNFα) therapeutic transgene expression cassette was incorporated into the phage genome. First, we found that human chondrosarcoma cells (SW1353) have high expression of αvβ3, αvβ5 integrin receptors, and both TNFα receptors. Targeted particle encoding a luciferase reporter gene efficiently and selectively mediated gene delivery to these cells. When SW1353 cells were treated with the targeted particle encoding a TNFα transgene, significant cell killing was evident and was associated with high expression of TNFα and apoptosis‐related genes. In vivo, mice with established human chondrosarcoma showed suppression of tumors upon repetitive intravenous administrations of the targeted phage. These data show that our phage‐based particle is a promising, selective, and efficient tool for targeted chondrosarcoma therapy.
Tsafa E, Bentayebi K, Topanurak S, et al., 2020, Doxorubicin improves cancer cell targeting by filamentous phage gene delivery vectors., International Journal of Molecular Sciences, Vol: 21, ISSN: 1422-0067
Merging targeted systemic gene delivery and systemic chemotherapy against cancer, chemovirotherapy, has the potential to improve chemotherapy and gene therapy treatments and overcome cancer resistance. We introduced a bacteriophage (phage) vector, named human adeno-associated virus (AAV)/phage or AAVP, for the systemic targeting of therapeutic genes to cancer. The vector was designed as a hybrid between a recombinant adeno-associated virus genome (rAAV) and a filamentous phage capsid. To achieve tumor targeting, we displayed on the phage capsid the double-cyclic CDCRGDCFC (RGD4C) ligand that binds the alpha-V/beta-3 (αvβ3) integrin receptor. Here, we investigated a combination of doxorubicin chemotherapeutic drug and targeted gene delivery by the RGD4C/AAVP vector. Firstly, we showed that doxorubicin boosts transgene expression from the RGD4C/AAVP in two-dimensional (2D) cell cultures and three-dimensional (3D) tumor spheres established from human and murine cancer cells, while preserving selective gene delivery by RGD4C/AAVP. Next, we confirmed that doxorubicin does not increase vector attachment to cancer cells nor vector cell entry. In contrast, doxorubicin may alter the intracellular trafficking of the vector by facilitating nuclear accumulation of the RGD4C/AAVP genome through destabilization of the nuclear membrane. Finally, a combination of doxorubicin and RGD4C/AAVP-targeted suicide gene therapy exerts a synergistic effect to destroy human and murine tumor cells in 2D and 3D tumor sphere settings.
Zhou JY, Suwan K, Hajitou A, 2020, Initial steps for the development of a phage-mediated gene replacement therapy using CRISPR-Cas9 technology, Journal of Clinical Medicine, Vol: 9, ISSN: 2077-0383
p53 gene (TP53) replacement therapy has shown promising results in cancer gene therapy. However, it has been hampered, mostly because of the gene delivery vector of choice. CRISPR-Cas9 technology (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) can knock out the mutated TP53 (mutTP53), but due to its large size, many viral vectors are not suitable or require implemented strategies that lower the therapeutic efficiency. Here, we introduced a bacteriophage or phage-based vector with the ability to target cancer cells and aimed to investigate the feasibility of using this vector to deliver CRISPR-Cas9 transgene in human lung adenocarcinoma cells. First, we produced a tumour-targeted bacteriophage carrying a CRISPR-Cas9 transgene cassette. Next, we investigated any negative impact on vector titers via quantitative polymerase chain reaction (qPCR) and colony-forming agar plate. Last, we combined Western blot analysis and immunofluorescence staining to prove cell transduction in vitro. We showed that the tumour-targeted bacteriophage can package a large-size vector genome, ~10 kb, containing the CRISPR-Cas9 sequence without any negative impact on the active or total number of bacteriophage particles. Then, we detected expression of the Cas9 in human lung adenocarcinoma cells in a targeted and efficient manner. Finally, we proved loss of p53 protein expression when a p53 gRNA was incorporated into the CRISPR-Cas9 phage DNA construct. These proof-of-concept findings support the use of engineered bacteriophage for TP53 replacement therapy in lung cancer.
Chongchai A, Suwan K, Yan W, et al., 2020, Targeted Gene Therapy Against Chondrosarcoma Using Superior Bacteriophage-Based Vector, 23rd Annual Meeting of the American-Society-for-Gene-and-Cell-Therapy, Publisher: CELL PRESS, Pages: 345-346, ISSN: 1525-0016
Waramit S, Suwan K, Asavarut P, et al., 2020, Targeted Cancer Gene Therapy Using a Superior Bacteriophage-Based Vector Encoding Interleukin-15, 23rd Annual Meeting of the American-Society-for-Gene-and-Cell-Therapy, Publisher: CELL PRESS, Pages: 336-337, ISSN: 1525-0016
Suwan K, Waramit S, Przystal J, et al., 2019, Next-generation of targeted AAVP vectors for systemic transgene delivery against cancer, Proceedings of the National Academy of Sciences of USA, Vol: 116, Pages: 18571-18577, ISSN: 0027-8424
Bacteriophage (phage) have attractive advantages as delivery sys-tems compared to mammalian viruses, but have been consideredpoor vectors because they lack evolved strategies to confrontand overcome mammalian cell barriers to infective agents. Wereasoned that improved efficacy of delivery might be achievedthrough structural modification of the viral capsid to avoid pre-and post-internalization barriers to mammalian cell transduction.We generated multifunctional hybrid AAV/phage (AAVP) particlesto enable simultaneous display of targeting ligands on the phage’sminor pIII proteins and also degradation-resistance motifs on thevery numerous pVIII coat proteins. This genetic strategy of directedevolution, bestows a next-generation of AAVP particles that fea-ture resistance to fibrinogen adsorption or neutralizing antibodies,and ability to escape endolysosomal degradation. This results insuperior gene transfer efficacyin vitroand also in preclinicalmouse models of rodent and human solid tumors. Thus, the uniquefunctions of our next-generation AAVP particles enable improvedtargeted gene delivery to tumor cells.
Przystal J, Waramit S, Pranjol MZI, et al., 2019, Efficacy of systemic temozolomide-activated phage-targeted gene therapy in human glioblastoma, EMBO Molecular Medicine, Vol: 11, Pages: 1-21, ISSN: 1757-4676
Glioblastoma multiforme (GBM) is the most lethal primary intracranial malignant neoplasm in adults and most resistant to treatment. Integration of gene therapy and chemotherapy, chemovirotherapy, has the potential to improve treatment. We have introduced an intravenous bacteriophage (phage) vector for dual targeting of therapeutic genes to glioblastoma. It is a hybrid AAV/phage, AAVP, designed to deliver a recombinant adeno‐associated virus genome (rAAV) by the capsid of M13 phage. In this vector, dual tumor targeting is first achieved by phage capsid display of the RGD4C ligand that binds the αvβ3 integrin receptor. Second, genes are expressed from a tumor‐activated and temozolomide (TMZ)‐induced promoter of the glucose‐regulated protein, Grp78. Here, we investigated systemic combination therapy using TMZ and targeted suicide gene therapy by the RGD4C/AAVP‐Grp78. Firstly, in vitro we showed that TMZ increases endogenous Grp78 gene expression and boosts transgene expression from the RGD4C/AAVP‐Grp78 in human GBM cells. Next, RGD4C/AAVP‐Grp78 targets intracranial tumors in mice following intravenous administration. Finally, combination of TMZ and RGD4C/AAVP‐Grp78 targeted gene therapy exerts a synergistic effect to suppress growth of orthotopic glioblastoma.
Przystal JM, Hajji N, Khozoie C, et al., 2018, Efficacy of arginine depletion by ADI-PEG20 in an intracranial model of GBM, Cell Death and Disease, Vol: 9, ISSN: 2041-4889
Glioblastoma multiforme (GBM) remains a cancer with a poor prognosis and few effective therapeutic options. Successful medical management of GBM is limited by the restricted access of drugs to the central nervous system (CNS) caused by the blood brain barrier (BBB). We previously showed that a subset of GBM are arginine auxotrophic because of transcriptional silencing of ASS1 and/or ASL and are sensitive to pegylated arginine deiminase (ADI-PEG20). However, it is unknown whether depletion of arginine in peripheral blood in vivo has therapeutic activity against intracranial disease. In the present work, we describe the efficacy of ADI-PEG20 in an intracranial model of human GBM in which tumour growth and regression are assessed in real time by measurement of luciferase activity. Animals bearing intracranial human GBM tumours of varying ASS status were treated with ADI-PEG20 alone or in combination with temozolomide and monitored for tumour growth and regression. Monotherapy ADI-PEG20 significantly reduces the intracranial growth of ASS1 negative GBM and extends survival of mice carrying ASS1 negative GBM without obvious toxicity. The combination of ADI-PEG20 with temozolomide (TMZ) demonstrates enhanced effects in both ASS1 negative and ASS1 positive backgrounds.Our data provide proof of principle for a therapeutic strategy for GBM using peripheral blood arginine depletion that does not require BBB passage of drug and is well tolerated. The ability of ADI-PEG20 to cytoreduce GBM and enhance the effects of temozolomide argues strongly for its early clinical evaluation in the treatment of GBM.
Bentayebi K, Hajitou A, 2018, A revised root for the human Y chromosome differentiation and diversity landscape among North African populations, Journal of Investigative Genomics, Vol: 5, Pages: 35-37, ISSN: 2373-4469
North Africa is a crucial area in the settlement history of modern humans because it represents a possible connection between Africa and Europe. So far, genetic data were inconclusive about the fact that this region constitutes a barrier to gene flow, as previous results were highly variable depending on the genetic locus studied. The present study evaluates the impact of North Africa in reducing gene flow between populations from Africa and Europe, by comparing formally various genetic loci in the Y chromosome and analyzing several parameters of population differentiation taking into account the effects of both demography and natural selection at some loci. The Y chromosome is inherited through the paternal line and remains virtually unchanged through many generations. The combination of the analysis of Y chromosome STR and SNP will allow the analysis of human evolution in paternal lineages in different time scales. The forensic implication of the results are discussed.
Chira S, Gulei D, Hajitou A, et al., 2018, Restoring the p53 'Guardian' Phenotype in p53-Deficient Tumor Cells with CRISPR/Cas9, Trends in Biotechnology, Vol: 36, Pages: 653-660, ISSN: 0167-7799
With an increasing prevalence in the human population, cancer has become one of the most investigated fields of medicine. Among the potential targets for cancer therapy is the tumor suppressor gene TP53, which is found in a mutated state in approximately 50% of human cancers and is often associated with poor prognosis. We propose a novel, highly tumor-specific delivery system for TP53, based on the CRISPR/Cas9 genome editing technology. This system will restore the normal p53 phenotype in tumor cells by replacing the mutant TP53 gene with a functional copy, leading to sustained expression of p53 protein and tumor regression.
Asavarut P, Suwan K, Chu G, et al., 2018, A Hybrid Phagemid-Derived Vector for Systemic Targeted Cancer Gene Therapy and Recombinant Virus Production, 21st Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), Publisher: CELL PRESS, Pages: 47-47, ISSN: 1525-0016
Namdee K, Khongkow M, Boonrungsiman S, et al., 2018, Thermoresponsive bacteriophage nanocarrier as a gene delivery vector targeted to the gastrointestinal tract., Molecular Therapy : Nucleic Acids, Vol: 12, Pages: 33-44, ISSN: 2162-2531
The use of the gastrointestinal tract as a site for the local delivery of DNA is an exciting prospect. In order to obtain an effective vector capable of delivering a gene of interest to target cells to achieve sufficient and sustained transgene expression, with minimal toxicity, we developed a new generation of filamentous bacteriophage. This particular bacteriophage was genetically engineered to display an arginine-glycine-aspartic acid (RGD) motif (an integrin-binding peptide) on the major coat protein pVIII and carry a mammalian DNA cassette. One unanticipated observation is the thermoresponsive behavior of engineered bacteriophage. This finding has led us to simplify the isolation method to purify bacteriophage particles from cell culture supernatant by low-temperature precipitation. Our results showed that, in contrast to non-surface modified, the RGD-modified bacteriophage was successfully used to deliver a transgene to mammalian cells. Our in vitro model of the human intestinal follicle-associated epithelium also demonstrated that bacteriophage particles were stable in simulated gastrointestinal fluids and able to cross the human intestinal barrier. In addition, we confirmed an adjuvant property of the engineered bacteriophage to induce nitric oxide production by macrophages. In conclusion, our study demonstrated the possibility of using bacteriophage for gene transfer in the gastrointestinal tract.
Hajitou A, Campbell S, Suwan K, et al., 2018, Selective inhibition of histone deacetylation in melanoma increases targeted gene delivery by a bacteriophage viral vector, Cancers, Vol: 10, ISSN: 2072-6694
The previously developed adeno-associated virus/phage (AAVP) vector, a hybrid between M13 bacteriophage (phage) viruses that infect bacteria only and human Adeno-Associated Virus (AAV), is a promising tool in targeted gene therapy against cancer. AAVP can be administered systemically and made tissue specific through the use of ligand-directed targeting. Cancer cells and tumor-associated blood vessels overexpress the αν integrin receptors, which are involved in tumor angiogenesis and tumor invasion. AAVP is targeted to these integrins via a double cyclic RGD4C ligand displayed on the phage capsid. Nevertheless, there remain significant host-defense hurdles to the use of AAVP in targeted gene delivery and subsequently in gene therapy. We previously reported that histone deacetylation in cancer constitutes a barrier to AAVP. Herein, to improve AAVP-mediated gene delivery to cancer cells, we combined the vector with selective adjuvant chemicals that inhibit specific histone deacetylases (HDAC). We examined the effects of the HDAC inhibitor C1A that mainly targets HDAC6 and compared this to sodium butyrate, a pan-HDAC inhibitor with broad spectrum HDAC inhibition. We tested the effects on melanoma, known for HDAC6 up-regulation, and compared this side by side with a normal human kidney HEK293 cell line. Varying concentrations were tested to determine cytotoxic levels as well as effects on AAVP gene delivery. We report that the HDAC inhibitor C1A increased AAVP-mediated transgene expression by up to ~9-fold. These findings indicate that selective HDAC inhibition is a promising adjuvant treatment for increasing the therapeutic value of AAVP.
Waramit S, Suwan K, Asavarut P, et al., 2017, The augmentation of tumour-associated antigen expression by a hybrid bacteriophage/AAV vector for CAR T cell therapy, European-Society-of-Gene-and-Cell-Therapy (ESCGT) Congress, Publisher: MARY ANN LIEBERT, INC, Pages: A39-A39, ISSN: 1043-0342
Hajitou A, Yata T, 2017, TETRAFUNCTIONAL BACTERIOPHAGE
Pasqualini R, Arap W, Gelovani J, et al., 2017, Methods and compositions related to adenoassociated virus-phage particles
Suwan K, Tsafa E, Przystal J, et al., 2017, A Hybrid Phage-AAV vector: the new partner for cancer combination chemotherapy, Annual Conference of the British-Society-for-Gene-and-Cell-Therapy / Joint UK-Regenerative-Medicine-Platform Meeting, Publisher: MARY ANN LIEBERT, INC, Pages: A21-A22, ISSN: 1043-0342
Albahrani M, Asavarut P, Suwan K, et al., 2017, Selective cytokine gene therapy for the treatment of paediatric brain cancer, Annual Conference of the British-Society-for-Gene-and-Cell-Therapy / Joint UK-Regenerative-Medicine-Platform Meeting, Publisher: MARY ANN LIEBERT, INC, Pages: A33-A33, ISSN: 1043-0342
Hajitou A, Asavarut P, Yata T, 2017, Phagemid Vector
Chira S, Gulei D, Hajitou A, et al., 2017, CRISPR/Cas9: transcending the reality of genome editing, Molecular Therapy : Nucleic Acids, Vol: 7, Pages: 211-222, ISSN: 2162-2531
With the expansion of the microbiology field of research, a newgenome editing tool arises from the biology of bacteria thatholds the promise of achieving precise modifications in thegenome with a simplicity and versatility that surpasses previousgenome editing methods. This new technique, commonlynamed CRISPR/Cas9, led to a rapid expansion of thebiomedical field; more specifically, cancer characterizationand modeling have benefitted greatly from the genome editingcapabilities of CRISPR/Cas9. In this paper, we briefly summarizerecent improvements in CRISPR/Cas9 design meant toovercome the limitations that have arisen from the nuclease activityof Cas9 and the influence of this technology in cancerresearch. In addition, we present challenges that might impedethe clinical applicability of CRISPR/Cas9 for cancer therapyand highlight future directions for designing CRISPR/Cas9 deliverysystems that might prove useful for cancer therapeutics.
Dobroff AS, D'Angelo S, Eckhardt BL, et al., 2016, Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes, Proceedings of the National Academy of Sciences of the United States of America, Vol: 113, Pages: 12780-12785, ISSN: 0027-8424
Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors.
Tsafa E, Albahrani M, Bentayebi K, et al., 2016, The natural dietary genistein boosts bacteriophage-mediated cancer cell killing by improving phage-targeted tumor cell transduction, Oncotarget, Vol: 7, Pages: 52135-52149, ISSN: 1949-2553
Gene therapy has long been regarded as a promising treatment for cancer. However, cancergene therapy is still facing the challenge of targeting gene delivery vectors specifically totumors when administered via clinically acceptable non-invasive systemic routes (i.e.intravenous). The bacteria virus, bacteriophage (phage), represents a new generation ofpromising vectors in systemic gene delivery since their targeting can be achieved throughphage capsid display ligands, which enable them to home to specific tumor receptors withoutthe need to ablate any native eukaryotic tropism. We have previously reported a tumorspecific bacteriophage vector named adeno-associated virus/phage, or AAVP, in which geneexpression is under a recombinant human rAAV2 virus genome targeted to tumors via aligand-directed phage capsid. However, cancer gene therapy with this tumor-targeted vectorachieved variable outcomes ranging from tumor regression to no effect in both experimentaland natural preclinical models. Herein, we hypothesized that combining the natural dietarygenistein, with proven anticancer activity, would improve bacteriophage anticancer safetherapy. We show that combination treatment with genistein and AAVP increased targetedcancer cell killing by AAVP carrying the gene for Herpes simplex virus thymidine kinase(HSVtk) in 2D tissue cultures and 3D tumor spheroids. We found this increased tumor cellkilling was associated with enhanced AAVP-mediated gene expression. Next, weestablished that genistein protects AAVP against proteasome degradation and enhancesvector genome accumulation in the nucleus. Combination of genistein and phage-guidedvirotherapy is a safe and promising strategy that should be considered in anticancer therapywith AAVP.
Suwan K, Tsafa E, Przystal J, et al., 2016, Hybrid AAV/Phage Vector Enhances Chemotherapy Efficacy Against Cancer, 19th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT), Publisher: Nature Publishing Group, Pages: S265-S266, ISSN: 1525-0024
Hajitou A, Yata T, 2016, BACTERIOPHAGE-POLYMER HYBRID
Donnelly A, Yata T, Bentayebi K, et al., 2015, Bacteriophage mediates efficient gene transfer in combination with conventional transfection reagents, Viruses-Basel, Vol: 7, Pages: 6476-6489, ISSN: 1999-4915
The development of commercially available transfection reagents for gene transfer applications has revolutionized the field of molecular biology and scientific research. However, the challenge remains in ensuring that they are efficient, safe, reproducible and cost effective. Bacteriophage (phage)-based viral vectors have the potential to be utilized for general gene transfer applications within research and industry. Yet, they require adaptations in order to enable them to efficiently enter cells and overcome mammalian cellular barriers, as they infect bacteria only; furthermore, limited progress has been made at increasing their efficiency. The production of a novel hybrid nanocomplex system consisting of two different nanomaterial systems, phage vectors and conventional transfection reagents, could overcome these limitations. Here we demonstrate that the combination of cationic lipids, cationic polymers or calcium phosphate with M13 bacteriophage-derived vectors, engineered to carry a mammalian transgene cassette, resulted in increased cellular attachment, entry and improved transgene expression in human cells. Moreover, addition of a targeting ligand into the nanocomplex system, through genetic engineering of the phage capsid further increased gene expression and was effective in a stable cell line generation application. Overall, this new hybrid nanocomplex system i) provides enhanced phage-mediated gene transfer, ii) is applicable for laboratory transfection processes and iii) shows promise within industry for large-scale gene transfer applications.
Abaitua F, Przystal J, Hajitou A, et al., 2015, Arginine deprivation using ADI-PEG20 leads to regression of an ASS1-ve intracranial GBM tumor in mice and potentiates gamma irradiation of ASS1+ve GBM in vitro, 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Pasqualini R, Millikan RE, Christianson DR, et al., 2015, Targeting the interleukin-11 receptor alpha in metastatic prostate cancer: A first-in-man study, Cancer, Vol: 121, Pages: 2411-2421, ISSN: 0008-543X
BACKGROUNDReceptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors (“vascular zip codes”) within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature.METHODSThe authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα–based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer.RESULTSBMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m2). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine.CONCLUSIONSThese biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a large
Yata T, Lee ELQ, Suwan K, et al., 2015, Modulation of extracellular matrix in cancer is associated with enhanced tumor cell targeting by bacteriophage vectors, Molecular Cancer, Vol: 14, ISSN: 1476-4598
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