Seite - 36 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Dawidczyketal. Nanomedicines for cancer therapy is to provide a surface coating of polyethylene glycol (PEG). Whilst PEG coating increases circulation time and hence can increase tumor accumulation, it also inhibits uptake by tumor cells (Barenholz, 2012). Furthermore, PEG coating slows but doesnotprevent adsorptionofopsonins thatpromoteuptakeby macrophages of the liver and spleen. Targetingmolecules such as immunoglobulin-G (IgG) antibodies are opsonins andhence promote clearanceby themononuclearphagocyte system(MPS) (Walkey and Chan, 2012). The conjugation of folate to lipo- somes significantly increases their uptake by tumor-associated macrophages (Turketal., 2004). FDA-APPROVEDNANOMEDICINES There are currently six FDA-approvednanomedicines (Table1): brentuximab vedotin and Trastuzumab emtansine, Doxil, DaunoXome, Marqibo, and Abraxane (Dawidczyk et al., 2014). Brentuximab vedotin and Trastuzumab emtansine are antibody-drug conjugates (ADCs), conceptually one of the simplest nanomedicines with an anticancer drug conjugated to a targeting molecule. Brentuximab targets the protein CD30, a glycosylated phosphoprotein expressed by B cells, including B-cell lymphomas, some leukemias, and melanoma cancer stem cells (Mullard, 2013; Sassoon and Blanc, 2013; Sievers and Senter, 2013). Trastuzumab targets the human epidermal growth factor receptor2(HER2)overexpressed inHER2positive breast cancer (Lu et al., 2012; Verma et al., 2012).Monomethyl auristan E (MMAE) (Brentuximab vedotin) and mertansine (Trastuzumab emtansine) are too toxic to be used alone and hence coupling to a targeting antibody reduces toxic side effects. Several drug molecules are conjugated to each antibody via a valine-citrulline cleavable linker (Brentuximab vedotin) or covalent linkage (Trastuzumab emtansine) that is enzymatically degraded in endosomes following uptake. The small number of FDA-approved ADCs highlights the difficulty in translating relatively simplenanomedicines to theclinic. Doxil, DaunoXome, and Marqibo are liposomal nanomedicines. Doxil is a pegylated liposome about 100nm in diameter andencapsulatingabout10,000doxorubicinmolecules (Barenholz, 2012). Encapsulationminimizes side effects, such as cardiotoxicity, associated with high doses of free doxorubicin. The concentration of doxorubicin in the liposomes is greater than the solubility limit and hence most of the drug is in the solid phase (Barenholz, 2012). The incorporation of cholesterol increases the bilayer cohesiveness and reduces leakage. These features minimize osmotic effects and contribute to stability, with more than 98% of the circulating drug remaining inside liposomes (Lasic et al., 1992; Gabizon et al., 1994, 2003). The polyethylene glycol coating is designed to give a long circulation half time and thereby increase tumor accumulation by the EPR effect (Immordino et al., 2006; Vllasaliu et al., 2014).While the Table1 |SummaryofFDA-approvednanomedicines. Platform Class Drug d(nm) Drug/carrier Keydesign feature(s) Problemaddressed ratio Brentuximabvedotin ADC Monomethyl auristanE ∼10 ≤8 Valine-citrulline linker cleavedbycathepsin in endosomes Monomethyl auristanE (MMAE) is too toxic tobe usedalone Trastuzumabemtansine ADC Mertansine ∼10 ≤8 Non-cleavable linker; releaseofdrugby proteolyticdegradationof antibody inendosomes Mertansine is too toxic to beusedalone Doxil Liposome Doxorubicin 100 10,000–15,000 Lipidencapsulation for highdrug/carrier ratio, polyethyleneglycol coating toevadeMPS, crystallizationofdrug in liposomeminimizes escapeduringcirculation Drug toxicity andadverse cardiacsideeffects DaunoXome Liposome Daunorubicin 50 ∼10,000 Nopolyethyleneglycol coating, targetedbyMPS resulting inslowrelease intocirculation Drug toxicity andadverse cardiacsideeffects Marqibo Liposome Vincristine 100 ∼10,000 Nopolyethyleneglycol coating, targetedbyMPS resulting inslowrelease intocirculation Drug toxicity andadverse sideeffects Abraxane Proteincarrier Paclitaxel 130 >10,000 Non-specificbindingof paclitaxel toalbumin Overcomesvery low solubilityofpaclitaxel Frontiers inChemistry | ChemicalEngineering August2014 |Volume2 |Article69 | 36