Seite - 37 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Dawidczyket al. Nanomedicines for cancer therapy mechanismsofuptake and release arenot known, evidence sug- gests that the liposomes are takenupby endocytosis (Seynhaeve etal., 2013). DaunoXome (Gill et al., 1996; Bellott et al., 2001; Lowis et al., 2006) andMarqibo (Bedikian et al., 2011; Silverman and Deitcher, 2013)are liposomal formulationsofdaunorubicinand vincristine, respectively. In contrast toDoxil, the design strategy forDaunoXomeandMarqibo is topromoteuptakeby theMPS, providinga reservoir fromwhich the freedrugcanenter circula- tion, similar toa slow infusion.This is achievedbynot including pegylated lipids in the liposomes (Gill et al., 1996; Bellott et al., 2001;SilvermanandDeitcher,2013).DaunoXomeisabout50nm in diameter (Gill et al., 1996), andMarqibo is about 100nm in diameter (SilvermanandDeitcher,2013). Abraxane, or nab-paclitaxel (nanoparticle albumin bound), is lyophilized human serum albumin non-specifically bound to paclitaxel (Miele et al., 2009). Paclitaxel has very low sol- ubility and is administered with the toxic non-ionic solvent Cremophor,whichcan lead to awide rangeof allergic reactions. Oninjection,Abraxaneparticlesdissociate intosmalleralbumin- paclitaxelcomplexesorunboundpaclitaxel (Yardley,2013).Since albuminisabundantincirculation,Abraxaneprovidesareservoir ofaverylowsolubilitydruginanon-toxicplatform.Theparticles areabout130nmindiameterandcontainabout10,000paclitaxel molecules (Mieleetal., 2009). The pharmacokinetics of these nanomedicines reflects their design (Table2).BrentuximabvedotinandTrastuzumabemtan- sine both have moderate areas under the curve (AUCs), rela- tively lowclearance, and long eliminationhalf-timesof 3–4days (Younes et al., 2010; Lorusso et al., 2011; Girish et al., 2012; Lu et al., 2012; Bradley et al., 2013). Doxil has high AUC, low clearance rate, small distribution volume, and a long elimina- tion half-time (Barenholz, 2012). These features are largely due to thepolyethyleneglycol coating thatprovidesextendedevasion of theMPS andminimizes distribution into peripheral tissues (Gabizon et al., 1994; Hubert et al., 2000; Lyass et al., 2000; Hong and Tseng, 2001; Hamilton et al., 2002). DaunoXome (Gill et al., 1996; Bellott et al., 2001; Lowis et al., 2006) and Marqibo (Bedikian et al., 2011; Silverman and Deitcher, 2013) have clearance rates about an order of magnitude larger than for the ADCs and Doxil, low distribution volumes, and short elimination half-times on the order of 10h. The larger AUC associated with DaunoXome is related to the larger dose range compared toMarqibo.Abraxane has a fast clearance rate, about twoordersofmagnitudes larger thanDaunoXomeandMarqibo, large distribution volume, and elimination half-time similar to DaunoXomeandMarqibo(Sparreboometal., 2005;Andoet al., 2012). The pharmacokinetics for Abraxane are similar to free paclitaxel andtheother freedrugs: lowAUC,highclearance rate, highdistributionvolume,andshorteliminationhalf-time. Overall it is evident that antibody drug conjugates or lipo- somes with a pegylated surface have long elimination half- times, typically of 3–4 days. Increasing elimination half-times is expected to increase tumor accumulation via the EPR effect. However, increased tumor accumulation does not necessarily implyimprovedefficacysinceprocessessuchastransport,uptake, drug release, and delivery to the appropriate cellular compart- mentarealldownstreamofextravasationbytheEPReffect. NANOPARTICLEPLATFORMS,TARGETINGMOIETIES NANOPARTICLEPLATFORMS The development of a broad range of nanoparticle platforms with the ability to tune size, composition, and functionality has provided a significant resource for nanomedicine (Table3) (Niemeyer, 2001; Duncan, 2006; Cho et al., 2008; Greco and Vicent, 2009; Yu et al., 2013). Nanoparticle platforms can be broadlycategorizedasorganic, inorganic, andhybrid. Organic nanoparticles have been widely explored for decades, yielding a large variety of materials, formulations, imaging modalities, cargo, and targets for cancer therapy. Table2 |Summaryofpharmacokinetics forFDA-approvednanomedicinesandcorresponding freedrugs fromhumanclinical trials. Drug Dosemg2/m AUC(mgh/L) CL (L/h) Vd(L) t1/2(h) References Brentuximabvedotin 90–110 3.2–4.9 0.071–0.075 8.2–10.2 106–144 Younesetal., 2010;Bradleyet al., 2013 Trastuzumabemtansine 10–160 0.6–28 0.023–0.070 1.7–3.5 31–98 Lorussoetal., 2011;Girishet al., 2012;Lu etal., 2012 Doxil 25–80 600–4900 0.023–0.045 2.1–6.4 42–90 Gabizonetal., 1994;Hubertet al., 2000; Lyassetal., 2000;HongandTseng,2001; Hamiltonetal., 2002 DaunoXome 10–190 17–1700 0.40–0.94 2.9–4.1 2.8–8.3 Gill et al., 1996;Bellott et al., 2001;Lowis et al., 2006 Marqibo 2.0–2.25 5–15 0.36–0.38 2.6–2.9 9.6–12 Bedikianet al., 2011;SilvermanandDeitcher, 2013 Abraxane 150–300 4–10 31–67 900–1700 11–26 Sparreboometal., 2005;Andoetal., 2012 Doxorubicin 15–72 0.5–3.8 25–72 250–1800 9–29 Erttmannetal., 1988; Jacquetet al., 1990; Piscitelli et al., 1993;Gabizonetal., 1994 Daunorubicin 40–120 1–19 110–150 200–450 9–24 Bellottetal., 2001;Krogh-Madsenetal., 2012 Paclitaxel 170–330 6–40 15–50 160–530 7.2–7.6 Sparreboometal., 2005 Inmost cases,data represent the rangeofmeanormedianvalues forobtained fromdifferentdoses. Forunit conversionweusedanaveragebodysurfaceareaof 1.7m2, anaveragebodyweightof60kg, andabloodvolumeof5L. www.frontiersin.org August2014 |Volume2 |Article69 | 37