Delivery vector

Although L. lactis represents a promising candidate for a live mucosal vector delivery system, some laboratories have further explored the capacity of other bacteria with better intrinsic propaties such as lactobacilli. Specific strains of lactobacilli have been characterized to possess probiotic properties (microorganisms that provide health benefits when consumed). Furthermore, some lactobaciUi species such as Lact. casei, Lact. acidophilus, Lact. gasseri, Lact. plantarum, and Lact. fermentum are able to persist for longer periods than L lactis in the GIT. Additionally, some species of lactobacilli are part of the microbiota that colonized the mammalian small intestine. The interaction of lactobacilli with the intestinal mucosa is an important factor because this enhances mucosal immune responses. Since the end of the 1990s, researchers have been exploiting these inherent properties of lactobacilli to make them an attractive alternative and safer delivery system for molecules and compounds with health benefit (Rush et al. 1995 Pouwels et al. 1996). 

Similar to L lactis, many genetic tools have been improved over the last decade for lactobacilli to produce heterologous proteins. Identically to L. lactis, lactobacilli have a thick cell wall, and there is huge molecular and biochemical interspecies variation among this genus. Despite the significant improvements made on the delivery of more than 50 molecules, lactobacilli are still difficult to transform and genetically manipulate (Pouwels et al. 1998 LeBlanc et al. 2013). 

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Kost, T. A., and Condreay, J. P. (2002). Recombinant baculovirases as mammalian cell gene-delivery vectors. Trends Biotechnol. 20 173—180. 

Ferreira, L.C., Ferreira, R.C. and Schumann, W. (2005) Bacillus subtilis as a tool for vaccine development from antigen factories to delivery vectors. Anais da Academia Brasileira de Ciencias, 77 (1), 113-124. 

Oupicky D, Parker AL, Seymour LW (2002) Laterally stabilized complexes of DNA with linear reducible polycations strategy for triggered intracellular activation of DNA delivery vectors. J Am Chem Soc 124 8-9... 

Using what is perhaps the most efficient laboratory-scale synthesis to-date, Frechet et al. have prepared a family of ABA hybrids with aliphatic ester dendron A blocks and PEG B block. These non-toxic hybrids are being tested as drug delivery vectors [47],... 

Singh R, Pantarotto D, McCarthy D, Chaloin O, Hoebeke J, Partidos CD, Briand JP, Prato M, Bianco A, Kostarelos K (2005) Binding and condensation of plasmid DNA onto functionalized carbon nanotubes Toward the construction of nanotube-based gene delivery vectors. J. Am. Chem. Soc. 127 4388 4396. 

Li S, Huang L. Functional polymorphism of liposomal gene delivery vectors lipoplex and lipopolyplex. In Janoff AS, ed. Liposomes Rational Design. New York Marcel Dekker, Inc., 1999 89. 

Audouy SA, de Leij LF, Hoekstra D, Molema G. In vivo characteristics of cationic liposomes as delivery vectors for gene therapy. Pharm Res 2002 19(11) 1599-1605. 

Genes can be introduced by the application of naked DNA alone however, better efficiency is achieved when the DNA is incorporated into a delivery vector. These delivery vectors consist of viral, those utilizing modified virus particles for DNA delivery, and nonviral, for which various chemicals are used to aid DNA packaging and delivery. Viral vectors confer significantly better transfection efficiency than nonviral vectors however, recently the toxicity and oncogenic side effects of viral vectors have become a major concern (6). Nonviral vectors do not have such serious side effects but lack the efficiency (7). 

Keller M, Harbottle RP, Perouzel E, et al. Nuclear localisation sequence tern-plated nonviral gene delivery vectors investigation of intracellular trafficking events of LMD and LD vector systems. Chembiochem 2003 4(4) 286-298. 

Gene transfer requires a delivery vector (retrovirus, adenovirus, liposome). 

Table 2.1. Brain concentration, blood-brain barrier PS product, and plasma AUC (0-60 min) of brain delivery vectors after i.v. bolus injection.

With regard to transport capacity, the introduction of the anti-human insulin receptor antibody (HIR MAb) 83-14 as a vector indicates the potential for future improvements in brain-specific delivery vectors. Compared to anti-TfR monoclonal antibodies, the brain de-hvery in primates is over 7-fold higher due to the high PS product of the HIR MAb. 

Figure 2.9. Differential pharmacological effect elicited by vector-mediated delivery of a VIP analogue. The organ blood flow in brain and salivary gland was measured in conscious rats after i.v. administration of vehicle (saline), the brain delivery vector OX26-SA, the VIP peptide alone, or the chimeric peptide. While cerebral blood flow increased in the chimeric peptide group by 60% compared to the saline control, the increase in salivary gland blood flow seen with the peptide alone was abolished by coupling to the vector. The VIP analogue was biotinylated with a non-cleavable 14-atom spacer (biotin-XX) for coupling to the vector. Data from reference [95].

To develop alkylglycoside moieties as drug delivery vectors, a systematic analysis was performed to identify the structural requirements for both vectors and drugs. This allowed us to understand the spectrum and limitations of compounds that can be delivered by this system. A binding study using isolated tubular membranes enabled the investigation of such struc-... 

Langer and coworkers synthesized a series of copolymers containing various amounts of diacrylate and amine monomers, investigating copolymer composition with the ability to act as transport DNA into cells. They screened 140 copolymers as synthetic gene-delivery vectors. Of these, 56 were able to bind DNA. These polymers were then screened for their ability to facilitate the transfer of plasmid DNA into a common monkey cancer cell line. Two of the copolymers with quite varied compositions showed good activity—one expected and the other unexpected. The expected copolymer composition would have been a selected composition in a typical search and the other would have been omitted. Thus, combinatorial-like approaches can offer unexpected results to problems. 

The library was screened for DNA-complexing materials as well as gene delivery vectors, revealing several new materials that were able to condense DNA... 

Kang HC, Lee M, Bae YH (2007) Polymeric gene delivery vectors. In Peppas NA, Hilt JZ, Thomas JB (ed) Nanotechnology in therapeutics Taylor and Francis, New York... 

Cullis, P.R., Chonn, A. (1998). Recent advances in liposome technologies and their applications for systemic gene delivery. Adv. Drug Deliv. Rev., 30(1-3), 73-83. Audouy, S.A., de LeiJ, L.F., Hoekstra, D., Molema, G. (2002). In vivo characteristics of cationic liposomes as delivery vectors for gene therapy. Pharm. Res., 19(11), 1599-1605. 

Read, M.L., Etrych, T., Ulbrich, K., Seymour, L.W. (1999). Characterisation of the binding interaction between poly(L-lysine) and DNA using the fluorescamine assay in the preparation of non-viral gene delivery vectors. FEBS Lett., 461(1-2), 96-100. 

Dash, P.R., Read, M.L., Fisher, K.D., et al. (2000). Decreased binding to proteins and cells of polymeric gene delivery vectors surface modified with a multivalent hydrophilic polymer and retargeting through attachment of transferrin. J. Biol. Chem., 275, 3793-3802. 

Ogris M, Carlisle RC, et al. Melittin enables efficient vesicular escape and enhanced nuclear access of nonviral gene delivery vectors. J Biol Chem 2001 276(50) 47550-47555. 

Li JY, et al. Genetically engineered brain drug delivery vectors cloning, expression and in vivo application of an anti-transferrin receptor single chain antibody-streptavidin fusion gene and protein. Protein Eng 1999 12(9) 787-796. 

Nevertheless, some issues have to be addressed before this approach can be applied. Firstly, the tyrosinase gene is quite large and would be difficult to add to a delivery vector. Secondly, melanin production may be too low in vivo for effective MR detection of its metal complex [100]. Finally, potentially high toxicity of melanin and its precursors could restrict the applicability of this reporter gene [99]. 

Fominaya, J., Gasset, M., Garcia, R., Roncal, F., Albar, J.P. and Bemad, A. (2000) An optimized amphiphilic cationic peptides as an efficient non-viral gene delivery vector. J. Gene Med., 2, 455 164. 

Figure 17.1 Chemical structures of poly cationic polymers used as gene delivery vectors.

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