Page - 75 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Conniotet al. Nanocarriers for immunecell targetingand tracking as particulate vaccine delivery systems, or immunomodulatory molecules is being widely investigated (Al-Hanbali et al., 2006; Hillaireau andCouvreur, 2009; Sharp et al., 2009; Shahar et al., 2010;Smithetal., 2012). Numerous studieshavedemonstrated that thesedeliveryplat- forms could increase the uptake of antigens and adjuvants by DCs, leading to better immune responses (Diwan et al., 2002; Schlosseret al., 2008;Florindoetal., 2009a). InvivoDC-targeted vaccines are able todeliver,within the sameplatform,bothanti- gens and additional stimuli (i.e., adjuvants) to the same cell in its natural environment, enhancing and maximizing the out- come (Kazzaz et al., 2006). Particulate delivery systems range frommicro andnanoparticles, liposomes, to virus-like particles (VLPs). Unlike ex vivo DC vaccines, the clinical intervention is limited to vaccine administration, sparing time in fastidious cyclesofbloodwithdrawal and invitrocell culture.Also, itoffers on-shelfproducts,whichcanbeproducedat large scalewithcost reductionandincreasedquality. NANOTECHNOLOGY-BASEDAPPROACHESASIMMUNECELL TARGETEDDELIVERYSYSTEMS Nano-based systems have been described as platforms for tar- geting and delivery of not only therapeutic agents, but also nanodevices and analytical systems for theranostics. The range of applicationsofnanosystems can includedrugdelivery, cancer and gene therapy, as well as imaging and cell tracking through biomarkers and biosensors (Rawat et al., 2006) (Supplementary Material). Nanosystems have been used to increase the resolu- tionofclinical imaging,with improvedsensitivityandspecificity, leadingtoearlierdiagnosticsandreal-timeresults.Thismayallow theuseofprophylacticmeasures, toavoidtheprogressof thedis- easeor togreaterefficacyof therapies,duetoanearlier treatment (Riehemannetal., 2009). Thedevelopmentofnano-basedsystemshasprovidedprotec- tion strategies for incorporated agents, such as biomolecules— nucleicacids,peptidesandproteins—whicharegenerallyquickly degradedwhen administered in vivo. Therapeutic agents can be embedded, encapsulated, or even adsorbed or conjugated onto thenanosystems,which canbemodifiedandassociated toother adjuvants toachieveanoptimizedreleaseprofile(Mahapatroand Singh, 2011). Usual concerns about the administration of these biomolecules have been eased, since lower doses are generally usedandamore restricteddistribution is achieved (Rawat et al., 2006).Infact, thewidelyrecognizedversatilityofnanotechnology strategies allows the accuratedesignofmultifunctionalnanocar- riers.These, in turn, canbe functionalizedby ligandsofdifferent natures to promote a targeted delivery of their cargo both at cellularandsubcellular level. Nanocarriers can also potentiate the cytosolic delivery of biomolecules as siRNA andmiRNA, important gene expression regulators,providingtheirescapefromendo-lysosomalcompart- ments. miRNAs are short oligonucleotides (18–22 nucleotides) and are involved in multiple pathways related to the devel- opment and differentiation of cells, and in the pathogen- esis of cancer, constituting a valuable target Chen et al., 2014b; Gajos-Michniewicz et al., 2014). However, its in vivo application demands the development of cell-specific delivery approachestopromotetheirbiologicaleffect,whicharecurrently underexplored. The modulation and regulation of the pathophysiology dynamics at the molecular level has enabled nanomedicines to achieve a disease control with an unprecedented precision. Therefore, several nano-based systems composed by diverse materials, and thus presenting different characteristics, have been proposed and sorted in polymeric, lipid, metal and inor- ganic nanocarriers (Figure2). Among them, it is important to underline liposomes, polymeric nanoparticles andmicelles and dendrimers. Besides the strong demand to develop alternative thera- peutic options to address unmet clinical needs, the novel nanotechnology-basedplatformshave although important chal- lenges, not only for industry but also for government agencies. Efficacyandsafetyareevaluatedonproof-of-conceptstudies,but themanufacturing processmust be robust by identifying all its criticalpointsandthus implementing“quality-by-design”(QbD) conceptor improvedprocessanalytical technologies (PAT). Liposomes Liposomesconsistofself-assembledlipidbilayermembraneswith size ranging from90 to 150nm,which are formedby phospho- lipids and cholesterol that enclose an aqueous core (Figure3A). Phospholipidsarecomposedbyhydrophilicheadsandhydropho- bic long tails. Thus, as previously described in several reviews, their structure allows hydrophilicmolecules to be incorporated within the inner compartments, while the hydrophobic com- poundswillbeentrappedwithin thehydrophobicbilayer (Sahoo andLabhasetwar,2003;Aslanetal., 2013;Sharmaetal., 2013). Thepotentialuseof liposomesasdelivery systems isbasedon the fact that they provide a slow and sustained release, improv- ing the accumulationof the entrappedmolecules. Also, on their ability to decrease cytotoxicity of incorporatedmolecules, since theymodulate the biodistribution and pharmacokinetics (Khan et al., 2008; Sharma et al., 2013).Having in consideration their biocompatibility, the biodegradability and ability to cross lipid bilayers and cell membranes, liposomes have been proposed as delivery platforms for vaccines, anticancer drugs and gene ther- apy (Ewert et al., 2005). However, one of themajor drawbacks of conventional liposomes is the short circulation time, being rapidly removed by mononuclear phagocytes of the reticular endothelial system (RES). Stealth liposomes, or long-circulating liposomes,havebeendeveloped toovercome thisproblem.They consist in liposomes that are sterically stabilized, presenting thus aprolongedhalf-life (Frank,1993;Krishnamachari etal., 2011). Regarding the success attained by liposomal platforms in the clinic and advanced-stage clinical trials, several liposomal-based delivery systems are nowadays offered as an anticancer strat- egy, such as liposomal doxorubicin, cytarabine and cisplatin (Abraham et al., 2005;Huwyler et al., 2008; Aslan et al., 2013). Theuseof liposomes fordoxorubicindeliveryprevents thedam- age of heart and renal healthy tissues that is usually induced by theextremetoxicityofthedrug(Abrahametal.,2005).Moreover, doxorubicinhas alreadybeen formulated in active targeted lipo- somesforbreastcancer therapy,usingengineeredpeptide ligands (Sharma et al., 2013). Other attractive approach is the use of Frontiers inChemistry | ChemicalEngineering November2014 |Volume2 |Article105 | 75