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Hindawi Publishing CorporationClinical and Developmental ImmunologyVolume , Article ID ,pageshttp://dx.doi.org/.//

Review ArticleChitin, Chitosan, and Glycated Chitosan Regulate ImmuneResponses: The Novel Adjuvants for Cancer Vaccine

Xiaosong Li,1 Min Min,2 Nan Du,1Ying Gu,3 Tomas Hode,4

Mark Naylor,5 Dianjun Chen,1 Robert E. Nordquist,4 and Wei R. Chen6

Department of Oncology, Te First Affiliated Hospital of Chinese PLA General Hospital, Beijing , China Department of Gastroenterology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing , China

Department of Laser Medicine, Chinese PLA General Hospital, Beijing , China ImmunoPhotonics Inc., Columbia, MO , USA Dermatology Associates of San Antonio, San Antonio, X , USADepartment of Engineering and Physics, University of Central Oklahoma, Edmond, OK , USA

Correspondence should be addressed to Wei R. Chen; [email protected]

Received September ; Revised December ; Accepted December

Academic Editor: Clelia M. Riera

Copyright Xiaosong Li et al. Tis is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

With the development o cancer immunotherapy, cancer vaccine has become a novel modality or cancer treatment, and the

important role o adjuvant has been realized recently. Chitin, chitosan, and their derivatives have shown their advantages asadjuvants or cancer vaccine. In this paper, the adjuvant properties o chitin and chitosan were discussed, and some detailedinormation about glycated chitosan and chitosan nanoparticles was also presented to i llustrate the trend or uture development.

1. Adjuvant

Activating the immune system or therapeutic benet haslong been a goal in immunology, especially in cancer treat-ment []. However, or the development o therapeutic

vaccines to treat cancer patients, there are still some obstaclesto overcome. Te tumor antigens are usually sel-derived andare, thereore, poorly immunogenic. umors develop escapemechanisms to avoid the immune system, such as tumor

editing, low or nonexpression o MHC class I molecules orsecretion o suppressive cytokines. Moreover, the immunesystems o cancer patients are ofen compromised, leadingto impaired mechanisms o antigen presentation, nonrespon-siveness o activated cells, and enhanced inhibition osel-reactivity by regulatory cells []. With the deeperunderstanding o the crosstalk between the host immunesystem and antigens, the important role o adjuvant in cancer

vaccine has been proposed [].

.. Concept and Classication of Adjuvant. Adjuvants arecompounds that stimulate the immune system and increasethe response to a vaccine, without having any specic

antigenic effect on their own []. Based on their principalmechanisms o action, adjuvants can be generally dividedinto two classes [, ]: () vaccine delivery systems, suchas mineral salts, emulsions, liposomes, and virosomes[]; () immunostimulatory adjuvants, including toll-likereceptor (LR) agonists (e.g., monophosphoryl lipid A),saponins, and cytokines [].

.. Mechanism of Adjuvant. Adjuvants exert their effectby several different mechanisms. Vaccine delivery systemscan help present antigens to the immune system o thehost in a more efficient way and control the release andstorage o the antigens. Immunostimulatory adjuvants affectthe immune system and increase the immune responses toantigens. Cytokine production is increased by the activationo MHC molecules, costimulatory signals, or through relatedintracellular signaling pathways, leading to the enhancedspecic immune response against antigens.

.. Commonly Used Adjuvants. It has been over yearssince the discovery o the adjuvant activity o aluminum
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Clinical and Developmental Immunology

OO

OO

O

NH2 NH2 NH2

HOHOHOHO

OH

OH

OHOH

F : Chemical structure o the chitosan molecule.

Because o its mucoadhesive properties, chitin and chi-tosan are widely applied or mucosal routes o administration,that is, oral, nasal, and ocular mucosa, which are noninvasiveroutes. Te enhancement o adaptive immune responsesto several antigens has been proved []. Recent clinicalstudies have conrmed that chitosan is a promising adjuvantplatorm or intranasal vaccination [, ]. Te mechanismso vaccine enhancementby chitosan through mucosal admin-

istration are believed to be due to both retention o vaccinein the nasal passages via mucoadhesion and opening oendothelial cell junctions or paracellular transport o vaccine[].

Several other routes or the administration o chitinand chitosan were proposed, such as intraperitoneal (i.p.),intravenous (i.v.), subcutaneous (s.c.), and intratumoral (i.t.)administrations []. Given by intravenous administra-tion, signicant priming effects o chitin particles in alveolarmacrophages and NK cells in mice were observed by Shi-bata et al. []. Phagocytosable small-sized chitin particlesactivated alveolar macrophages to express cytokines such asIL-, tumor necrosis actor- (NF), and IL-, leading

to INF- production mainly by NK cells. Tey urtherdemonstrated that the cytokine production was throughmannose receptor-mediated phagocytosis [].

okura et al. proved that macrophages were activatedto various extents by chitin derivatives, and % DA-chitinand chitin sulate stimulate the production o circulatingantibodies[]. Accumulation o carboxymethyl chitin tookplace in granulocytes and macrophages. Tey also oundout that intraperitoneal injection o N-acetylchitohexaoseinhibited the growth o tumor cells and pathogens.

Chitin has complex and size-dependent effects on innateand adaptive immune responses, which include the ability torecruit and activate innate immune cells and induce cytokine

and chemokine production []. Te involved cell suracereceptors include macrophage mannose receptor, toll-likereceptor (LR-), C-type lectin receptor Dectin-, andleukotriene B receptor (BL) [].

Da Silva et al. demonstrated in their experiment thatchitin particles using intraperitoneal injection were potentmultiaceted adjuvants that induced adaptive T, T, andT immune responses []. LR-, MyD, and IL-Ahave been proved to play important roles in the adjuvantproperties o chitin and chitosan [].

Te immune response induced by chitin and chitosan isdetermined by the existence o antigen. Marcinkiewicz et al.ound that i.p. administration o chitosan alone enhanced

humoral responses but not cell-mediated immune responsesin mice []. Subcutaneous administrations o chitosanwithout antigen were ound to be ineffective. In other studies,Seerian and Martinez ound that chitosan particles, ormu-lated in an emulsion with antigen, squalene, and PluronicL, gave a prolonged, high antigen-specic antibody titerand sensitized animals or antigen-specic DH responsesollowing an i.p. injection [].

It is believed that chitosan enhances both humoral andcell-mediated immune responses. Zaharoff et al. exploredchitosan solution as an adjuvant or subcutaneous vaccina-tion o mice with -galactosidase, a model protein antigen[]. Tey ound that chitosan enhanced antigen-specicantibody titers over veold and antigen-specic splenicCD+ prolieration over sixold. Strong increases in anti-body titers together with robust delayed-type hypersensitiv-ity (DH) responses revealed that chitosan induced bothhumoral and cell-mediated immune responses. Tey alsocompared chitosan with traditional vaccine adjuvants andproved that chitosan was equipotent to incomplete Freundsadjuvant (IFA) and superior to aluminum hydroxide. It was

hypothesized that a viscous chitosan solution, when admin-istered subcutaneously, would not only provide immunestimulation as previously described but also act as an antigendepot [].

Recombinant granulocyte-macrophage colony-stimula-ting actor (rGM-CSF) expedites neutrophil recovery incancer patients receiving chemotherapy. When coormulatedwith chitosan, local rGM-CSF retention at a subcutaneousinjection site in mice was increased or up to days [].In contrast, when delivered in a saline vehicle, rGM-CSFwas undetectable in h []. Tis indicated that chi-tosan helped control the dissemination o rGM-CSF. IL- is a potent antitumor cytokine that exhibits signicant

clinical toxicities afer systemic administration. When givenin tumor-bearing mice, intratumoral administration o IL- coormulated with chitosan (chitosan/IL-) could helplimit its systemic toxicity, by increasing local retention oIL- in the tumor microenvironment (chitosan/IL- versusIL- alone: - days versus - days) []. Moreover, theenhancement o antitumor efficacy o chitosan/IL- andchitosan/rGM-CSF was observed by Zaharoff et al. [,].

4. Chitosan Derivatives: Glycated Chitosan

Many chitosan derivatives, such as trimethyl chitosan, Zwit-terionic chitosan, and glycated chitosan, have been invented

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recently []. With the development o nanotechnology,chitosan have shown its unique advantages when combinedwith nanoparticles. Improved biodegradability, immunolog-ical activity, and high viscosity can be achieved by modica-tion o chitosan, which makes them excellent candidates asadjuvants.

Chitosan is soluble in diluted acids but is relativelyinsoluble in water [,]. Te poor solubility o chitosanposes limitations or its biomedical applications. Especiallyin the areas o immunology, an aqueous solution is essentialor its use as an immunostimulant in clinical applications.By attaching galactose molecules to the chitosan molecules,a new water-soluble compound, glycated chitosan (GC), wasormed [,].

GC was synthesized by incubating an aqueous suspensiono chitosan with a threeold excess o galactose and subse-quent stabilization by borohydride reduction o the Schiffbases and Amadori products []. GC is a synthesized non-toxic biodegradable product, which is the drug component oinCVAX (Immunophotonics Inc., Columbia, MO), which hasbeen also reerred to as laser immunotherapy (LI). LI usesa combination o local laser irradiation and local administra-tion o GC at either primary or metastatic tumor sites[].Employing synergistic photothermal effect and immuno-logical effect, laser immunotherapy has been proved to bea promising treatment modality or metastatic cancers[].Trough intratumoral administration, GC is usually givenafer laser irradiation o the tumor lesions. GC exerts its effectas immunoadjuvant or treatment o metastatic cancers [].

During laser irradiation, the temperature in the treatedlesion could reach up to C[]. Te irradiated tumorcells would swell and break into pieces by thermal effect,creating antigen sources to stimulate the host immune sys-tem to generate tumor-specic immune responses [, ].Tese antigens include tumor-associated antigens, thermallyinduced heat shock proteins (HSPs), and a large amount osel-antigens. Antigen presenting cells (APCs), particularlydendritic cells (DCs), can capture these antigens and migrateto lymph nodes, where they present these antigens to cells,thus activating cytotoxic -lymphocytes (CLs) [].

Heat shock proteins, including calreticulin (CR),HSP, and gp, have been shown to act as potentimmunoadjuvants to enhance antigen-specic tumorimmunity []. HSPs can promote the cross-presentationo HSP-bound peptide antigens to major histocompatibilitycomplex (MHC) class I molecules in DCs, leading to

induction o antigen-specic CL [, ]. It is proposedthat GC exerts its effect through the pathway similar to thato chitin and chitosan [, ]. It has been also observedthat NF-and INFsecretion was increased when mousemacrophages were incubated with GC, which was also clearlydose dependent [,].

Animal experiments showed that LI using GC couldhave a high potential or the treatment o metastatic tumorsby inducing a tumor-specic, long-lasting immunity [].Primary tumors and metastases began to regress about sev-eral weeks afer LI in successully treated rats. Furthermore,these successully treated tumor-bearing rats could resistrepeated challenges with the tumors o same type and also

escalated tumor doses. Passive adoptive transer was urtherperormed using splenocytes as immune cells and the spleencells harvested rom successully treated tumor-bearing ratsprovided % immunity in the naive recipients []. Tepassively protected rst cohort rats were immune to tumorchallenge with an increased tumor dose; their splenocytes

also prevented the establishment o tumor in the secondcohort o naive recipient rats. In another experiment, Balb/Cmice bearing EM tumor achieved long-term tumor-specic response, which helps the successully treated miceresist repeated tumor rechallenge [].

A clinical trial or the treatment o late-stage breastcancer patients, who have ailed other available modalities,has been carried out recently[]. It has been proved thatLI is well tolerated, which allows repeated LI applications.Te most common adverse effects were rash and pruritusat the treatment sites. No grade toxicity was observed.Preliminary results showed that LI was capable o reducingthe size o treated primary breast tumors and untreatedmetastases in the lungs [].

GC has shown several advantages when working asan immunoadjuvant in LI []. Local application o GCinduces low toxicity, which makes it suitable or late-stagecancer patients who cannot tolerate chemotherapy and radia-tion therapy[, ]. It also can be applied repeatedly withoutdose limiting effect. By combination with laser irradiation,signicant systemic antitumor immunity is generated [,]. Improved survival time or metastatic cancer patients isobserved in clinical trial [].

5. Chitosan Nanoparticles

Improved biodistribution, increased specicity and sensi-tivity, and reduced pharmacological toxicity are achievedby combining chitosan with nanoparticles, making themperect polymeric platorms or the development o newpharmacological and therapeutic drug release systems [].Chitosan nanoparticles (CNPs) can be administratedthrough noninvasive routes such as oral, nasal, pulmonary,and ocular routes []. Moreover, CNPs have been proposedas nonviral vectors in gene therapy and have shown theiradjuvant effect in vaccines []. CNPs are also used orchemotherapy drug delivery by combining them withmonoclonal antibody with reduction o drug side effects insome specic cancer patients [].

CNP may be a sae and efficacious adjuvant candidatesuitable or therapeutic vaccines. Experimental results haveproved that CNP had a strong potential to increase bothcellular and humoral immune responses and elicited a bal-ancedT/T response. Wen et al. investigated the promotedimmune response to ovalbumin (OVA) in mice by CNP andits toxicity []. Te mice were immunized subcutaneouslywith OVA alone or with OVA dissolved in saline containingQuil A, chitosan, or CNP. CNP did not cause any cell mortal-ity or side effects. Tey observed that the serum OVA-specicIgG, IgG,IgGa, andIgGb antibody titersand ConA-, LPS-,and OVA-induced splenocyte prolieration were signicantlyenhanced by CNP as compared with OVA and chitosan

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groups. CNP remarkably increased the killing activities oNK cells activity []. CNP also signicantly promoted theproduction o T (IL- andIFN-) andT (IL-) cytokinesand upregulated the mRNA expression o IL-, IFN-, andIL- cytokines in splenocytes rom the immunized micecompared with OVA and chitosan groups[].

Wu et al. showed that humoral and cellular immunitieswere signicantly enhanced in immunized mice, whichresisted the inection oE. coli and survived, while the controlmice maniested evident symptoms and lesions o inection[]. Teir results showed that the inoculation with CpG-CNP signicantly raised the content o IgG, IgM, and IgAin the sera o immunized mice. Increased number o whiteblood cells and lymphocytes and elevated levels o IL-, IL-,and IL- were also observed in the mice o CpG-CNP group.It indicates that CpG-CNP can be utilized as an effectiveadjuvant to improve the immunoprotection and resistance oporcine against inectious disease[].

Modied chitosans can be used or the wide rangeo biomedical applications including the interaction andintracellular delivery o genetic materials []. Its uniqueproperties help orm a complex with siRNA []. Chitosan-based nanoparticles have been considered as a potentialcarrier or various gene delivery applications, which indicateits promising perspectives in gene therapy.

6. Conclusions

Chitin and chitosan derivatives are well-tolerated, effectiveadjuvants with considerable potential or clinical practice.Te immune response induced by chitin and chitosan isdetermined by the existence o antigen. It is believed that

chitosan enhances both humoral and cell-mediated immuneresponses when vaccinated with antigen.

Glycated chitosan apparently possesses improved proper-ties over chitin and chitosan or immunological stimulationin clinical studies. However, more work needs to be done todissectthe signalingpathways andthe effectson host immunecells, which will help understand the molecular mechanismsinvolved in the induction o adaptive immune responsesinduced by GC.

Combining with laser photothermal interaction andpossibly other treatment modalities, GCs effects can besignicantly enhanced when treating late-stage, metastaticcancers, as shown in preclinical and clinical studies. Further

investigations are needed to understand the mechanisms oLI with GC and to explore optimal treatment protocols oruture clinical applications.

Authors Contribution

X. Li and M. Min contributed equally to this work.

Acknowledgments

Tis work was supported in part by Grants rom NationalNatural Science Foundation o China (no. ), Bei-

jing Municipal Science and echnology Commission (no.

Z), and the First Affiliated Hospital o Chi-nese PLA General Hospital (no. ZD).

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