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Engineering Nanoparticles to Overcome Barriers to Immunotherapy
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
Nanoparticles targeted to dendritic cells using monoclonal antibodies against CD40, DEC-205 (C-type lectin), and CD11c (integrin receptor) were able to stimulate IL-12 production and co-stimulatory marker CD86 more effectively than nontargeted nanoparticles [122]. Nanoparticles for immunotherapy can also be targeted to dendritic cells and macrophages through functionalization with mannose, which binds to the mannose receptor (CD206). Mannose conjugation to nanoparticles coloaded with tumor vaccines and TLR adjuvants elevated interferon-y levels in the spleen and slowed tumor proliferation in comparison to untargeted nanoparticles [45]. The success of this approach is not limited to mannose; a galactosylated cationic dextran has also been used to formulate nanoparticles that can deliver oligo-nucleotides to tumor-associated macrophages 2.5 times more efficiently than their ungalactosylated counterparts [46].
Characterization of Biosimilar Biologics
Published in Laszlo Endrenyi, Paul Jules Declerck, Shein-Chung Chow, Biosimilar Drug Product Development, 2017
The variations in galactosylation observed in health and disease suggest that it is either of functional significance or an epiphenomenon. The increase in galactosylation in pregnancy is particularly intriguing as it coincides with FcRn-mediated transcytosis of IgG from mother to fetus in the third trimester (Alavi et al., 2000; Bondt et al., 2013; Einarsdottir et al., 2013; Jefferis, 2012; Kibe et al., 1996; Kobata, 2008). Although studies, in vitro, have not revealed a relationship between the natural glycoform of IgG-Fc and FcRn binding, the glycoform at the single glycosylation site in human FcRn does show this relationship (Natsume et al., 2008). The possible consequences for hypogalactosylated recombinant antibodies on in vivo activity have been extrapolated from in vitro cell-based assays and animal experiments. Removal of terminal galactose residues from Campath-1H was shown to reduce classical complement activation but to be without effect on FcγR-mediated functions (Boyd et al., 1995). Similarly, the ability of rituximab to kill tumor cells by the classical complement route has been shown to be maximal for the [G2F]2 glycoform, in comparison to the [G0F]2 glycoform (Raju and Jordan, 2012). The product that gained licensing approval was composed of ∼25% galactosylated oligosaccharides; therefore, the level of galactosylation is a CQA for some mAbs and must be maintained, within limits, over the lifetime of the drug. It may also be an indicator and measure of control over the production process. In the absence of galactose, the terminal sugar residue is N-acetylglucosamine, which may be accessible to bind the mannose receptor, expressed on many cell types, including antigen presenting dendritic cells. Similarly, immune complexes formed with agalactosylated IgG may bind the mannan binding lectin (MBL) and activate the lectin complement pathway (Arnold et al., 2006; Jefferis, 2012; Malhotra et al., 1995).
Macrophage Targeting: A Promising Strategy for Delivery of Chemotherapeutics in Leishmaniasis and Other Visceral Diseases
Published in Sarwar Beg, Mahfoozur Rahman, Md. Abul Barkat, Farhan J. Ahmad, Nanomedicine for the Treatment of Disease, 2019
Jaya Gopal Meher, Pankaj K. Singh, Yuvraj Singh, Mohini Chaurasia, Anita Singh, Manish K. Chourasia
MRs is a group of transmembrane receptors, are highly expressed on the surface of macrophage. These are from the CD 206 group and are mainly of C-type 1 and C-type 2. MRs have become a major area of macrophage drug targeting owing to the very specific feature of recognizing mannose and fucoseglyco conjugates that are broadly found on the surface of many pathogens. MRs are well known for their primary function of intracellular transport of MTB and also for antigen uptake and presentation. MRs has sialic acid residues on N-linked glycans which is very crucial for its binding to glycoproteins (sulfated and mannosylated). Pathogens like Leishmania donovani has glycan (with mannose terminal) on their surface and hence is recognizable to macrophages. Based on this information, mannose receptor targeting of chemotherapeutics has become a useful tool in treatment of visceral diseases (Irache et al., 2008). Our own group has developed and evaluated mannose grafted chitosan nanocapsules carrying amphotericin B for anti-leishmanial activity. The mannose decorated nanocapsules were observed to be highly internalized by infected macrophage when compared to non-decorated nanocapsule. Further studies revealed higher localization as well as accumulation of amphotericin B in the macrophage-rich visceral organs (liver and spleen) (Asthana et al., 2015). Zhu and co-workers (2011) developed mannose modified chitosan treated PLGA nanoparticles. They investigated the uptake ability of developed nanoparticles as a function of incubation time and concentration of nanoparticles. It could be concluded that the developed novel nanoparticles had high binding affinity and internalization capacity. Gao et al. (2013) have prepared PEGtidedendrons, and decorated them with alpha-d-mannopyranosyl-phenylisothiocyanate. They have reported a 12-fold higher uptake by surface coated dendrons than unmodified dendrons in murine macrophage.
Conjugating doxorubicin to polymannose: a new strategy for target specific delivery to lung cancer cells
Published in Journal of Biomaterials Science, Polymer Edition, 2019
Arul Prakash Francis, A. Jayakrishnan
Polysaccharides with unique properties such as biocompatibility, biodegradability, affinity towards the specific receptors and non-toxicity are widely used as drug carriers [10–12]. The aqueous solubility and the pharmacokinetics such as bioavailability, plasma half-life, biodistribution, metabolism, and elimination of water-insoluble drugs could be enhanced by conjugating with polysaccharides [13]. Some properties of the polysaccharide-drug conjugates such as the molecular weight (MW), polydispersity, charge and structural conformations are reported to influence the pharmacokinetics. Furthermore, the polysaccharides with high MW can increase the residence time as well as bio-distribution by reducing the elimination rate [12]. Although many naturally occurring polysaccharides are an important class of biomaterials, their antigenicity due to the presence of trace amounts of proteins limit their clinical use, especially as drug delivery systems. Moreover, the regulatory agencies treat the drug-polysaccharide conjugates as new chemical entities, and consistent and reproducible physical and chemical properties are required for their approval, which is difficult to achieve with natural polymers [14]. However, synthetic polysaccharides can be prepared from naturally occurring monomers to mimic the structure and function of biological polymers [15], with reproducible chemical and physical properties and without immunogenicity [16]. The polysaccharide of mannose namely mannan, from natural sources possesses target specificity towards the mannose receptor [17]. Targeting macrophages with mannose receptors [18, 19] using polymannose (PM)-drug conjugates may increase the possibility of targeting macrophage-associated diseases like cancer.
Synthetic polymannose as a drug carrier: synthesis, toxicity and anti-fungal activity of polymannose-amphotericin B conjugates
Published in Journal of Biomaterials Science, Polymer Edition, 2018
Arul Prakash Francis, Sneha Gurudevan, A. Jayakrishnan
Mannan, the linear polysaccharide of mannose derived from natural sources has been reported to possess target specificity towards the mannose receptor [22]. Macrophages possess mannose receptors [23] and therefore, targeting macrophages using polymannose (PM)-drug conjugates may open up the possibility of targeting macrophage-associated diseases in a more efficient manner [24].