Review
Targeting tumor antigens to dendritic cells using particulate carriers

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Abstract

Dendritic cells play a central role in antigen presentation and generation of cytotoxic T lymphocyte (CTL) response required for anticancer vaccination. The review focuses on use of particulate carriers like lipid and polymeric nanoparticles for targeting tumor antigens to the dendritic cells. The role of various physicochemical parameters of nanocarriers such as size, surface charge in passive targeting is detailed. Utilization of different ligands such as mannose, Fc receptor, CD11c/CD 18, DEC-205 and DC-SIGN on DC for active targeting is reviewed. Smart nanocarriers such as pH sensitive nanocarriers, pre forming liposomes, cell penetrating peptide containing systems and virosomes that can specifically increase the CTL response generating greater antitumor immunity have also been discussed.

Introduction

Dendritic cells (DCs) play a central role in primary immune activation as they are the main antigen presenting cells (APCs) of the immune system. During their routine surveillance in peripheral tissues, immature DCs (iDCs) take up antigens, which are subsequently processed and presented on MHC (major histocompatibility complex) molecules to other cells of the immune system. This leads to activation of one or more of the various arms of the immune system causing either immune activation or tolerance. For the induction of immunity it is essential that the iDCs are activated by adjuvant to express essential co-stimulatory molecules and inflammatory cytokines that allow optimal presentation and priming of immune cells. Thus, simply by stimulating the DCs in proper manner immunity can be triggered, making DCs the “target of choice” for antigen delivery in vaccination. One of the bottlenecks in DC-mediated vaccination is the delivery of sufficient amounts of antigens to DCs in a way that leads to proper immune activation avoiding tolerance [1], [2]. A well-established clinical procedure to overcome this is ex vivo loading of DCs with antigens and subsequent reinfusion of antigen-loaded DCs into patients [3], [4], [5]. FDA has approved a DC-based therapeutic cancer vaccine in the year 2010 for the treatment of metastatic asymptomatic hormone refractory prostate cancer [6]. Several others are in late phases of clinical trials (e.g. Activartis invented DCs based vaccine for aggressive brain cancer). However, these methods are labor intensive, costly and often requires autologous cells from individual patients, making its application limited. Particulate systems loaded with antigens and targeted to DCs may provide an attractive pharmaceutical approach to overcome this limitation, as they can be prepared at large scale and under GMP conditions [7].

In addition, such particulate carriers offer several advantages for DC-targeted vaccination compared to soluble antigens. Their particulate nature mimics pathogens such as bacteria and viruses more closely and thus they have a higher chance of properly activating DCs. They can increase the amount of antigen that can be delivered to the DCs. They can also form a long lasting antigen delivery depot system delivering prime and booster doses in vaccination schedules. A particulate carrier can protect the antigen against premature degradation, thus reducing the quantity of antigen needed to evoke an effective immune response. Lastly, in vivo targeting using particulate carriers gives the opportunity to co-deliver adjuvants along with the antigens, to enhance maturation of the DC or modulate the immune response. Particulate carriers allow both the antigen and the adjuvant to be delivered to the same APCs. Several studies have shown beneficial effects of this co-delivery approach [8], [9], [10].

A large variety of particulate carriers have been investigated for their capability to stimulate the immune system against cancer. These delivery systems vary in their composition (natural and/or synthetic components), physicochemical characteristics (e.g. size, charge), type of antigen, and the route of administration.

The purpose of this review is to summarize the literature related to the use of particulate carriers to deliver protein or peptide-based antigens (but no DNA) to DCs for therapeutic vaccination against cancer thus establishing an update for scientists working in this field.

Section snippets

Role of DCs in antigen presentation and immunity

DCs are derived from hemopoietic bone marrow progenitor cells which initially transform into iDCs. The main DC populations which have been identified in humans are DCs derived from myeloid precursors (myDCs), such as monocytes, which include interstitial DCs, and plasmacytoid (pDCs) or lymphoid DCs (lDCs), which are primarily found in blood and secondary lymphoid organs.

iDCs are in constant surveillance for antigens. They capture, process and subsequently present antigenic epitopes on their

Targeting antigens to DCs using particulate carriers

The inherent capacity of DCs to take up particulate matter can be exploited for the targeted delivery of antigens to these antigen-presenting cells. Antigens carried via a particulate carrier can enter DCs via various uptake pathways depending on their size, charge, surface properties or the presence of specific targeting ligands [15] (also see Section 5). Entry into DCs is largely governed by biological mechanisms of endocytosis, including the uptake of large particles (0.25–10 μm) by

Lipid based particulate carriers

Lipid based carriers are the mainstay of antigen delivery to dendritic cells because of their obvious advantages of biocompatibility and the possibility to tailor adjuvant effects. Among those, phospholipid membrane vesicles (i.e. liposomes) have been widely used because of their marked absence of toxicity and a low intrinsic immunogenicity. Liposomes can be easily varied in size and lipid composition, thereby changing the adjuvant properties of these carriers. Moreover, surface charge of

Actively targeted particulate carriers

The use of receptor-ligand interactions to obtain specific binding and uptake of antigen delivery systems by DCs can be a good approach to increase the amount of antigen that can be delivered into DCs. Different DC-specific and selective receptors have been used for this purpose. A review by Tacken et al. [69] summarizes the different receptors present on DCs and the possibilities to target them. Here, some of the receptor targeted systems that have been described in literature will be

Smart particulate carriers

Besides ligand-targeted particulate carriers, more advanced carriers have been developed that are aimed at delivering their antigen cargo into the cytosol of DCs and other APCs. This makes MHC class I presentation pathway accessible for exogenously administered antigens and thereby increasing induction of CTL responses. Some examples of such smart carriers are given below and in Table 3.

Future perspectives

As described in the various sections of this review, a large number of particulate carriers are available for antigen delivery to DCs. Uptake of particulate nanocarriers with or without surface-conjugated targeting ligands by DCs has been demonstrated in vitro and in vivo in animal studies. However, the focus of the majority of these studies was on demonstrating immune activation without focusing on the underlying mechanisms that lead to DCs activation. As a consequence, critical factors for DC

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