Elsevier

Journal of Controlled Release

Volume 320, 10 April 2020, Pages 239-252
Journal of Controlled Release

Review article
Mannosylated nanocarriers mediated site-specific drug delivery for the treatment of cancer and other infectious diseases: A state of the art review

https://doi.org/10.1016/j.jconrel.2020.01.046Get rights and content

Highlights

  • Surface-modified nanocarriers are promising to overcome the lack of specificity and off-target effects of conventional nanocarriers.

  • Targeting the mannose receptors through the development of mannosylated nanocarriers is one of the most extensively studied approaches for the treatment of cancer and other infectious diseases.

  • Manuscript initially provides the introduction to C-type lectin receptors and their structural and binding properties. It covers the expression, distribution, and roles of mannose receptors.

  • It provides a detailed account of different mannosylated nanocarrier formulations.

  • Mannosylated nanocarriers depicted site-specific targeting, enhanced pharmacokinetic/pharmacodynamic profiles, and improved transfection efficiency of the drug.

Abstract

The non-modified nanocarriers-based therapies for the treatment of cancer and other infectious diseases enhanced the chemical stability of therapeutically active agents, protected them from enzymatic degradation and extended their blood circulation time. However, the lack of specificity and off-target effects limit their applications. Mannose receptors overexpressed on antigen presenting cells such as dendritic cells and macrophages are one of the most desirable targets for treating cancer and other infectious diseases. Therefore, the development of mannosylated nanocarrier formulation is one of the most extensively explored approaches for targeting these mannose receptors.

The present manuscript gives readers the background information on C-type lectin receptors followed by the roles, expression, and distribution of the mannose receptors. It further provides a detailed account of different mannosylated nanocarrier formulations. It also gives the tabular information on most relevant and recently granted patents on mannosylated systems.

The overview of mannosylated nanocarrier formulations depicted site-specific targeting, enhanced pharmacokinetic/pharmacodynamic profiles, and improved transfection efficiency of the therapeutically active agents. This suggests the bright future ahead for mannosylated nanocarriers in the treatment of cancer and other infectious diseases. Nevertheless, the mechanism behind the enhanced immune response by mannosylated nanocarriers and their thorough clinical and preclinical evaluation need to explore further.

Introduction

The term ‘nano’ has opted from the Latin word ‘nanus’ which means dwarf. Nanotechnology is the science, engineering, and technology in which controlled modification of at least one of the characteristics of the material/system/device is done by reducing the size to the nanometer scale [1].

In the healthcare system, nanotechnology is applicable in terms of nanomedicine and pharmaceutical nanotechnology. Nanomedicine is the stream of nanotechnology in the interest of health and the welfare of life. In other words, nanomedicine is the branch of nanotechnology which deals with the prevention, diagnosis, and treatment of the diseases and various traumatic injuries and thus preserve and increase human health. Pharmaceutical nanotechnology is the branch in which nanotechnology is applied in the design and development of drug delivery systems, devices, and diagnostic agents. For the drug delivery purpose, formulations ranging from 1 to 1000 nm are generally considered as nanoparticles or nanocarriers [2,3]. To achieve the desired therapeutic effect, nanocarriers must reach to the anticipated site of action with negligible loss during circulation and without hampering the adjacent healthy tissues. These desired characteristics can be incorporated within the nanocarriers by using efficient targeting approaches [4].

Passive targeting and active targeting techniques are most widely used for this purpose. Passive targeting can be achieved by changing the size and surface properties of the nanocarriers, and by taking the benefit of an altered microenvironment and increased permeability and retention (EPR) effect in the case of tumour cells [[5], [6], [7], [8]]. Active targeting can be achieved by surface modification of nanocarriers with particular ligands which represent their targeting towards a particular cell type because of receptor-mediated specificity. This decreases toxicity and off-target effects [3,7]. Development of mannose-coated nanocarriers is one of the widely investigated approaches for targeting mannose receptors (MRs) expressed on antigen presenting cells (APCs) such as dendritic cells and macrophages for the treatment of cancer and other infectious diseases. Different terms such as mannose-coated nanocarriers, mannose–conjugated nanocarriers and mannose-derived nanocarriers are used alternatively in the manuscript for mannosylated nanocarriers.

The current manuscript focuses on the fundamental concepts of C-type lectin receptors (CLRs) regarding their structures, conformations, and binding specificities. Subsequently, it elaborates on the mannose receptors specifically about their roles, expression, and distribution. Further, it gives a detailed account of various mannosylated nanocarrier systems. Finally, it covers the most relevant and recent patents granted on mannose-derived formulations.

Section snippets

C-type lectin receptors (CLRs)

C-type lectin receptors (CLRs) are considered as Ca2+ dependent carbohydrate recognition proteins. These receptors express single or multiple carbohydrate recognition domains (CRDs) on their C-type lectin-like domains (CTLDs). The components of the CLR family bind to different carbohydrates such as mannose, fucose, glucose, maltose, N-acetyl-D-Glucosamine (NAG), and the carbohydrates those present on the outer walls of the pathogens through one or more carbohydrate recognition domains (CRDs) in

Mannose receptors: expression and distribution

Mannose receptors (MRs) belong to the C-type lectin receptors (CLRs) superfamily expressed in the mice or humans and possess the mannose-binding ability. MRs mainly expressed in tissue macrophages which include fixed macrophages of the liver (Kupffer cells), lungs (alveolar macrophages), connective tissue (histiocytes), macrophages of the red pulp of the spleen, subcapsular sinus of the lymph nodes, bone marrow, and brain (microglia) cells [16,17]. MRs also expressed by the dendritic cells

Roles of mannose receptors

The role of MRs change based on their pattern and level of expression in different cells. MRs mediate the phagocytosis and endocytosis of the mannosylated compounds and the carbohydrate bearing microorganisms such as yeasts, mycobacteria, Gram-negative and positive bacteria, and parasites [17]. Fig. 2 provides the outline of mannose-receptor mediated endocytic and phagocytic pathways.

In endocytosis, all MR recognizing antigens (components) are engaged via motifs in their cytoplasmic domains

Surface characteristics of mannosylated nanocarriers: important considerations

In the design of mannosylated nanocarriers for active targeting via MR-mediated endocytosis, the density of the ligands plays an important role. Also, the chemical and physicochemical characteristics of nanocarriers should offer positive charge and mannose structures should be recognized by the MRs present on the infected macrophages [20]. Kawakami et al synthesized a novel mannosylated cholesterol derivative, cholesten-5-yloxy-N-(4-((1-imino-2-β-D-thiomannosyl-ethyl)amino)butyl) formamide

A detailed account on mannosylated nanocarriers

Based on the diversity of the materials available, different mannosylated nanocarrier systems have been developed so far those can be broadly classified as organic nanocarriers such as lipid-based nanocarriers, polymeric nanocarriers, cyclodextrin complex, and inorganic nanocarriers. These include liposomes, solid lipid nanoparticles, nanostructured lipid carriers, polymeric nanoparticles, polymeric microspheres, polymeric micelles, niosomes, quantum dots, dendrimers, cyclodextrin

Patents related to mannosylated formulations in recent years

Ample of work on the mannosylated formulations were carried out in recent years and patented under various patenting agencies. Here, we have carried out a patent search specifically on the World Intellectual Property Organization (WIPO) patent search database. We have shortlisted ten most relevant and recent patents published on mannose-derived formulations. Important details related to these patents are summarized in Table 2 [[89], [90], [91], [92], [93], [94], [95], [96], [97], [98]].

Summary and conclusion

A wide range of mannosylated nanocarriers were formulated by the association of the nanocarriers with the mannose, in which nanocarriers acted as a reservoir for therapeutically active components and mannose derivative acted as a targeting moiety.

The overall review of research work irrefutably confirmed the impact of mannosylation of the nanocarriers. Mannosylation of the nanocarriers showed specific targeting towards desired cell population without hampering to healthy cells, high binding

Funding

This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

Authors declare no conflict of interest.

Acknowledgment

Authors are grateful to Chancellor, NMIMS (Deemed-to-be University) and management of SVKM's NMIMS, School of Pharmacy and Technology Management, Shirpur for providing various reprographic sources for implementing this work.

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