magnetic resonance imaging ( mri ) is a clinical diagnostic modality based on differences in the longitudinal and transverse relaxation rates ( 1/t1 or 1/t2 ) of water protons in different tissues ( liang and lauterbur 2000 ) . contrast agents have been developed and used to enhance mr image contrast and to improve diagnostic accuracy . paramagnetic metal chelates , eg , gd(iii ) , fe(iii ) , and mn(ii ) complexes , can alter the relaxation rate of the surrounding water protons to allow for more effective mri contrast enhancement ( caravan et al 1999 ) . gd(iii ) chelates with high stability , eg , gd - dtpa , gd - dota , or their derivatives , have been mainly developed as mri contrast agents , which increase both 1/t1 and 1/t2 relaxivities ( weinmann et al 1984 ; magerstadt et al 1986 ; hayne et al 1989 ) . currently , gd - containing contrast agents are used in approximately 30% of mri examinations . these low - molecular - weight agents rapidly extravasate from the vasculature and nondiscriminatively distribute in the extracellular space . the agents have a very short blood half - life and a short time window for contrast - enhanced imaging . in many situations it is difficult to estimate the timing for optimal imaging , impeding accurate diagnostic imaging . macromolecular contrast agents are prepared by the conjugation of gd(iii ) dtpa , dota complexes , or their derivatives to synthetic polymers ( schuhmann - giampieri et al 1991 ; bogdanov et al 1993 ; wiener et al 1994 ; kobayashi and brechbiel 2004 ; langereis 2004 ) or natural macromolecules ( lauffer and brady 1985 ; wang et al 1990 ; sirlin et al 2004 ) , or by copolymerization of the low - molecular - weight contrast agents ( kellar et al 1997 ; ladd et al 1999 ; duarte et al 2001 ) . these agents have a long blood circulation time and can preferentially accumulate in solid tumor tissue depending on the hyperpermeability of the tumor vasculature ( gerlowski and jain 1986 ; hobbs et al 1998 ) . as a result , they provide superior contrast enhancement in the blood pool and in solid tumor tissue in animal models ( gossmann et al 1999 ; turetschek et al 2001 ; de lussanet et al 2005 ) . a number of macromolecular gd(iii ) complexes have been investigated as blood - pool contrast agents ( schuhmann - giampieri et al 1991 ; bogdanov et al 1993 ; shibata et al 1995 ; van beers et al 1995 ; roberts et al 1997 ; kobayashi et al 2001b ; li et al 2001 ; lee 2003 ; sirlin et al 2004 ) . these agents show molecular - weight - dependent or size - dependent plasma half - lives ( vexler et al 1994 ; kobayashi et al 2001a , b ) , and agents with higher molecular weights and longer blood half - life produced the better contrast enhanced vascular imaging . higher - molecular - weight chelates were prepared to increase their intravascular retention time for longer and clearer visualization of the neovascularity of neoplastic tissue ( weissleder et al 2001 ) . macromolecular agents with relatively high molecular weight ( > 20 kda , linear size ) have a potential to detect and characterize individual tumors more specifically and accurately due to their ability to measure tumor microvascular permeability , microvascular density , and vascular recruitment . albumin-(gd - dtpa ) ( 92 kda ) does not accumulate in benign tumors , but can gradually diffuse into the interstitial spaces of malignant tumors , which may be useful to accurately differentiate between these tumors ( gossmann et al 1999 ; van dijke 1996 ) . although macromolecular gd(iii ) complexes have clear advantages as blood - pool contrast agents , their slow body clearance is also a disadvantage with respect to toxicity . free gd(iii ) ions are highly toxic , with an ld50 as low as 0.5 mmol / kg in rat models ( weinmann et al 1984 ) . the dissociation of gd(iii ) complexes and release of gd(iii ) ions can be lethally toxic ( cacheris et al 1990 ) . the longer body retention time increases the probability of metabolism of the macromolecular complexes and release of gd(iii ) ions . the clearance rate decreases with the increase of molecular weight of the contrast agents ( kobayashi 2003 ) . it has been reported that a gd - dtpa polypropyleneimine dendrimer ( generation 2 ) conjugate ( 7 kda ) resulted in the retention of 45% of injected dose in rats 14 days after injection ( wang 2003 ) . the conjugation of gd - do3a to carboxylmethyl hydroxylethyl starch resulted in a macromolecular agent ( 72 kda ) that had about 47% of injected dose detected in rat body 7 days after the injection ( helbich et al 2000 ) . because of this safety concern , clinical development of macromolecular contrast agents has been limited . biodegradable polymers including poly(l - lysine ) , dextrans , and proteins have been used in the synthesis of macromolecular contrast agents . however , in vivo degradation of these materials takes place primarily in intracellular enzymatic compartments . mri contrast agents are mostly extracellular agents and have low cellular uptake . in addition , the extensive chemical conjugation on the polymers can significantly reduce their biodegradability ( crepon et al 1991 ) . consequently , contrast agents prepared from these polymers have longer body retention times and result in significant accumulation of gd ions in tissues ( bogdanov et al 1993 ; franano et al 1995 ; helbich et al 2000 ) . innovative approaches are needed for the design and development of safe , effective macromolecular contrast agents for clinical application . we have recently designed and developed novel extracellular biodegradable macromolecular gd(iii ) complexes based on polydisulfides to facilitate gd(iii ) elimination and to minimize its tissue retention ( lu et al 2004 ) . these complexes act as macromolecular agents for mr contrast enhancement and rapidly excrete as low - molecular - weight gd(iii ) chelates after the macromolecules are broken down by the endogenous thiols via the disulfide - thiol exchange reaction . here , we summarize the rationale of the biodegradable macromolecular contrast agents , their physicochemical and biological properties , and in vivo contrast enhancement in animal models . the ideal mri contrast agent would be an agent able to accumulate in the tissue of interest long enough for imaging with conventional or dynamic mri , then rapidly clear from the body . currently available mri contrast agents are primarily low - molecular - weight gd(iii ) chelates , which have transient tissue retention and clear rapidly from the body . we hypothesize that the incorporation of biodegradable structures into the backbone of macromolecules containing gd(iii ) chelates can result in mri contrast agents that will provide sufficient blood pool and tissue retention for effective contrast enhanced mr imaging . the structures will then react with biomolecules present in plasma or tissues to break down the macromolecules into smaller gd(iii ) complexes that can be readily excreted ( lu et al 2004 ) . free thiols including cysteine , glutathione ( gsh ) , cysteinylglycine ( cys - gly ) , and homocysteine are important endogenous biomolecules , with a total concentration of 15 m in human blood plasma and about 10 mm in the cytoplasm ( andersson et al 1995 ; deneke 2000 ) . we have incorporated disulfide bonds into the backbone of macromolecular gd(iii ) complexes to prepare biodegradable macromolecular mri contrast agents . the disulfide bonds in the polymer chains can be readily cleaved by the thiols via disulfide - thiol exchange reaction to break down the macromolecules into smaller gd(iii ) complexes , which can be excreted through renal filtration . since gd(iii ) chelates are mostly extracellular agents and the plasma thiol concentration is low , the degradation of the macromolecular agents is a slow process , which allows the agents to reside for an acceptable period in the circulation for effective contrast - enhanced mr imaging . the concept of extracellular biodegradable macromolecular mri contrast agents was validated with the first polydisulfide agent , gd - dtpa cystamine copolymers ( gdcc ) ( lu et al 2004 ) . gdcc was gradually degraded into smaller gd(iii ) complexes by the cleavage of the disulfide bonds in the polymer backbone via the disulfide - thiol exchange reaction in the presence of 15 m cysteine ( figure 1 ) . gdcc resulted in more significant and prolonged contrast enhancement in the cardiovascular systems in rat than a clinical agent , gd-(dtpa - bma ) , and excreted rapidly via renal filtration . degradation of gd - dtpa cystamine copolymers ( gdcc ) in the presence of cysteine . the structure of the polydisulfides can be readily modified to alter the physicochemical properties , pharmacokinetics , and in vivo contrast enhancement of the biodegradable mri contrast agents . the chemistry of cystine is more versatile and the carboxylic groups in cystine can be further modified to design and prepare biodegradable macromolecular contrast agents with different properties ( mohs et al 2004 ; zong et al 2005 ) . different substituents have been attached to cystine ( figure 2 ) , and the modified agents demonstrated different degradability , pharmacokinetics , and in vivo contrast enhancement . the chemistry , physicochemical and pharmaceutical properties , and in vivo contrast enhancement of the polydisulfide agents are discussed in the following sections . abbreviations : oet , ethoxy group ; peg , poly(ethylene glycol ) ; gdcep , gd - dtpa cystine diethyl ester copolymer . the synthetic procedure of polydisulfide gd(iii ) complexes is described in figure 3 with gdcc as an example . dtpa dianhydride is first copolymerized with a disulfide - containing diamine , eg , cystamine or cystine , by condensation copolymerization under basic conditions to give a polymeric ligand . dimethyl sulfoxide was used as the solvent and triethylamine as the base for the monomers soluble in organic solvent . for cystine , which is not soluble in organic solvent , the copolymerization was performed in aqueous solution of sodium carbonate or sodium hydroxide . polydisulfide gd(iii ) complexes are then prepared by the complexation of the polymeric ligands with gdcl3 or gd(oac)3 at ph 56 . the ph of the reaction mixture with gdcl3 decreases significantly during the complexation because of the release of hcl , and naoh is added to maintain the ph at 56 . . the molecular weight of polydisulfides from the condensation copolymerization can be as high as 100 000 da . there is a significant decrease of apparent molecular weight of copolymers after complexation with gd(iii ) because of the change of hydrodynamic volume of the copolymers after complexation . once the polydisulfide ligands chelate with gd , the polydisulfide gd(iii ) complexes are neutral or less charged and have reduced hydrodynamic volume . physicochemical parameters of some polydisulfide gd(iii ) complexes abbreviations : peg , polyethylene glycol ; gdcc , gd - dtpa cystamine copolymer ; gdcp , gd - dtpa cystine copolymer ; gdcep , gd - dtpa cystine diethyl ester copolymer ; mw , averaged molecular weight ; mn , averaged molecular number . the structure of polydisulfide gd(iii ) complexes have been modified by grafting peg of different lengths to the carboxylic groups in gd - dtpa cystine copolymers ( gdcp ) ( mohs et al 2004 , 2005 ) . monomethoxy - peg amine ( mpeg - nh2 ) was attached to gdcp in the presence of a coupling agent , 1-ethyl-3-(3-dimethylaminopropyl ) carbodiimide hydrochloride , in aqueous solution ( figure 4 ) . the grafting degree can be readily manipulated by altering the ratio of mpeg - nh2 to gdcp . the modification increases apparent molecular weights of the copolymers at a low grafting degree depending on the size of peg . further increase of grafting degree with peg of the same size does not further increase apparent molecular weight of the copolymers . abbreviations : mpeg - nh2 , monomethoxy - peg amine ; nhs , n - hydroxyl - succinimide ; edc , 1-ethyl-3-(3-dimethylaminopropyl ) carbodiimide hydrochloride . the coordination feature of gd(iii ) in the polydisulfide complexes is the same as that in gd-(dtpa - bma ) , a clinical mri contrast agent . the gd(iii ) is coordinated to 3 tertiary amine nitrogen atoms , 3 carboxylic groups , and 2 carbonyl groups of the amides of the dtpa bisamide . gd-(dtpa - bma ) is a nonionic agent and has low acute toxicity in mice ( ld50 = 14.8 mmol / kg ) because of high stability and low transmetallation with ca ( cacheris et al 1990 ) . the paramagnetic chelates decrease both t1 and t2 relaxation times , or increase the relaxation rates of surrounding water protons , resulting in increased signal intensity in t1-weighted imaging and decreased signal intensity in t2-weighted imaging . the chelates have a more significant effect on the relaxation rate of water protons in the coordination sphere of gd(iii ) ions , less effect on water molecules immediately surrounding the chelate , and little direct effect on the bulk water molecules . therefore , an effective gd(iii ) chelate contrast agent should have at least one coordination site for water molecules . the complexed water molecule rapidly exchanges with bulk water , resulting in efficient relaxation of bulk water . the net change of the relaxation rate of water protons depends on the concentration of gd(iii ) chelates and water exchange rate at the coordination site . relaxivity is the measurement of the efficiency of a contrast agent to change the relaxation rate and can be determined from the equation ( 1/ti)obs = ( 1/ti)d + ri[gd ] ( i = 1 , 2 ) , where ( 1/ti)obs refers to the measured relaxation rate , ( 1/ti)d the relaxation rate without a contrast agent , and ri the t1 or t2 relaxivity . polydisulfide gd(iii ) complexes have higher t1 relaxivity than gd-(dtpa - bma ) and the relaxivity varies based on the structure of the complexes ( table 1 ) . gdcc , gdcp , and gd - dtpa cystine diethyl ester copolymer ( gdcep ) have similar relaxivity in the range of 4.56.5 mmsec . it appears that the degree of pegylation in poly(ethylene glycol ) ( peg)-modified gdcp has a more significant impact on its relaxivity than the peg chain length . peg - gdcp copolymers with different peg lengths have similar relaxivity at the same grafting degree ( mohs et al 2005 ) . for peg - gdcp copolymers with the same peg length ( 2000 da ) , the t1 relaxivity of peg2000-gdcp with grafting ratios of 0.33 , 0.76 , and 1.2 mms decreases from 16.3 to 12.7 , and 8.73 mms , respectively . a high density of peg on the backbones of the copolymers may interfere with the interaction of water molecules to the gd(iii ) complexes because peg can associate with water molecules via hydrogen bonding ( mohs et al 2004 ) . polydisulfide gd(iii ) complexes with different structures demonstrate different degradation characteristics in the presence of cysteine . there was no degradation of gdcp in the incubation with 15 m cysteine for 6 hours at ph 7.4 and 37 c . gdcc gradually degraded under the same conditions and its molecular weight decreased approximately 28% , 33% , and 50% at 5 , 15 , and 60 minutes in the reaction ( lu et al 2004 ) . the degradation of gdcep was relatively slow in the first 60 minutes of incubation compared with gdcc , and its molecular weight decreased approximately 6% , 11% , and 24% at 5 , 15 , and 60 minutes . both gdcc and gdcep degraded into smaller oligomers and complexes at 6 hours ( zong et al 2005 ) . figure 5 shows size exclusion chromatograms of gdcep in the incubation with 15 m cysteine at ph 7.4 and 37 c . all three macromolecular agents degraded more rapidly at higher cysteine concentration ( 150 m ) and completely degraded into the smallest repeat units in the incubation with an excess of cysteine , which was verified by mass spectrometry . gdcp and gdcep are more sterically hindered around the disulfide bonds than gdcc , resulting in slower degradation . gdcp also has negative charges around the disulfide bonds at neutral ph , which further impede the access of the negatively charged cysteine to the disulfide bonds ( hupe and wu 1980 ) . therefore , little reduction of the disulfide bonds in gdcp occurs at low cysteine concentrations . the molecular weight distribution of gd - dtpa cystine diethyl ester copolymers ( gdcep ) in the incubation with 15 m l - cysteine at 37 c . the modification of gdcp also resulted in macromolecular agents with different degradability based on the length of peg chains ( mohs et al 2004 , 2005 ) . the peg - modified gdcp was stable at low cysteine concentration ( circa 10 m ) , similar to gdcp , and degraded with increased cysteine concentration . it appears that gdcp modified with short peg chains degraded more rapidly than that with long chains . the structural modification resulted in macromolecular agents with different degradability towards the disulfide - thiol exchange reaction , which may have different pharmacokinetic properties and in vivo contrast enhancement . polydisulfide gd(iii ) complexes should be able to circulate in the vasculature for an acceptable time window for effective contrast - enhanced mr imaging and then clear from the body with minimal long - term tissue retention of toxic gd(iii ) ions . pharmacokinetic data are the quantitative measurement of the circulation , excretion , and retention of the biodegradable macromolecular contrast agents in the body . a pharmacokinetic study showed that the low - molecular - weight agent gd-(dtpa - bma ) rapidly extravasated from the vasculature , while gdcc had a higher plasma concentration in the first few minutes ( approximately 515 minutes ) post injection at the same dose ( 0.1 mmol - gd / kg ) in rats ( figure 6 ) . the size of the biodegradable macromolecular agent affected the initial plasma concentration of the agent , but not the clearance from the vasculature . gdcc with high molecular weight ( mw = 60 000 da ) had a higher plasma concentration in the initial period ( circa 5 minutes ) after the injection than gdcc with low molecular weight ( mw = 18 000 da ) . the plasma concentration of gdcc with both molecular weights reached the same level at 20 minutes post injection . because the breakdown of the macromolecules is gradual , gdcc of the high molecular weight may produce relatively large molecules and remain in the blood at high concentration in the early stages of degradation . the large molecules eventually degrade into smaller complexes that are readily cleared via renal filtration . plasma pharmacokinetics of gd(iii ) complexes in rats after intravenous injection of gd-(dtpa - bma ) (  ) , gdcc-18 ( 18 kda ,  ) , and gdcc-60 ( 60 kda ,  ) at a dose of 0.1 mmol - gd / kg abbreviations : gdcc , gd - dtpa cystamine copolymer . most of the degradation products were cleared in the urine via renal glomerular filtration and more than 50% of injected gdcc was excreted in the first 4 hours post - injection , similar to gd-(dtpa - bma ) . consequently , rapid degradation and excretion of gdcc resulted in minimal retention of gd(iii ) in the major organs and tissues 10 days post - injection , which was at the same level as gd-(dtpa - bma ) ( wang et al 2005 ) . for example , carboxymethyl hydroxyethyl starch-(gd - do3a ) still had approximately 47% of injected dose in the body of experimental animals seven days after injection ( helbich et al 2000 ) . the degradation products of gdcc in the urine samples were identified as monomeric and oligomeric gd(iii ) complexes by mass spectrometry . it appears that the in vivo degradation of the polydisulfide gd(iii ) complexes was more complicated than the simple disulfide - thiol exchange reaction . most of the gd(iii ) complexes identified in the mass spectra were further metabolized after the cleavage of the disulfide bonds . the degradation products have a mass higher than the molecular weight of gd - dtpa ( mw = 547.6 da ) , the basic chelating unit of the agent , suggesting that the agent was excreted as stable gd(iii ) chelates after degradation . these results have demonstrated that the polydisulfide agents have a relatively long blood circulation as macromolecules in the blood pool at the early stage after injection and then degrade into smaller gd(iii ) complexes that excrete rapidly from the body . the polydisulfide gd(iii ) complexes present superior contrast enhancement in the cardiovascular systems and tumor tissue compared with the low molecular - weight agent , gd-(dtpa - bma ) , as shown in animal models . figure 7 shows the 3d maximum - intensity - projection ( mip ) , contrast - enhanced mr images of rats with gd-(dtpa - bma ) and gdcc with molecular weights of 18 000 and 60 000 da ( 0.1 mmol - gd / kg ) . gdcc of both molecular weights resulted in strong contrast enhancement in rat heart and vasculature at 2 minutes post injection and the signal intensity gradually decreased . gd-(dtpa - bma ) was rapidly extravasated from the vasculature and the contrast enhancement was much less at 2 minutes post - injection than with gdcc . gdcc with higher molecular weight resulted in more significant contrast enhancement in the small blood vessels than gdcc with lower molecular weight . strong contrast enhancement was observed in rat kidneys and then the urinary bladder with gdcc , indicating that the biodegradable macromolecular agent was eliminated from renal filtration and accumulated in the urinary bladder . the contrast enhancement in the cardiovascular system returned to background levels at 15 minutes post - injection while the signal intensity in the bladder significantly increased . three - dimensional maximum intensity projection ( mip ) mr images of rats before ( a ) and 2 ( b ) , 5 ( c ) , 10 ( d ) , and 15 ( e ) minutes after intravenous injection of gd-(dtpa - bma ) ( a ) , gd - dtpa cystamine copolymer gdcc-18 ( b ) , and gdcc-60 ( c ) at a dose of 0.1 mmol - gd / kg . structural modification of polydisulfide agents altered in vivo contrast enhancement . pegylation of gdcp resulted in more significant and prolonged contrast enhancement in the blood pool than gdcp . peg2000-gdcp at a grafting ratio of 0.76 produced stronger and longer contrast enhancement in the blood pool than peg2000-gdcp of a lower grafting ratio ( 0.33 ) , even if the latter had higher relaxivity ( mohs et al 2004 ) . both agents were more effective in contrast - enhanced blood - pool imaging than gdcp ( mw = 11 400 da ) ( figure 8) . with similar grafting ratios , peg - gdcp with different peg sizes had similar contrast enhancement in the blood pool during the initial period ( 2 minutes ) post - injection , but the duration of the contrast enhancement decreased with decreasing size of peg ( figure 9 ) . peg2000-gdcp resulted in more sustained enhancement than peg1000-gdcp , while peg550-gdcp had the least duration of enhancement . coronal mr images of mouse hearts before ( a ) and 1 ( b ) , 5 ( c ) , 15 ( d ) , 30 ( e ) , and 60 minutes ( f ) post intravenous injection of pega - gd - dtpa cystine copolymer ( gdcp ) ( a ) , pegb - gdcp ( b ) , gdcp ( c ) , and dtpa - bma ( d ) . polymeric agents were given at a dose of 0.03 mmol / kg and dtpa - bma was given at the standard clinical dose of 0.1 mmol - gd / kg . coronal mr images of mouse hearts before ( a ) and 2 ( b ) , 5 ( c ) , 15 ( d ) , 30 ( e ) , and 60 minutes ( f ) post intravenous injection of peg2000-gd - dtpa cystine copolymer ( gdcp ) ( a ) , peg1000-gdcp ( b ) , and peg500-gdcp ( c ) at a dose of 0.05 mmol - gd / kg . in tumor mri , the polydisulfide agents resulted in significant contrast enhancement in the tumor periphery . figure 10 shows the coronal mr images of tumor tissue contrast enhanced by gdcc , gdcp , gdcep , and gd-(dtpa - bma ) in mice bearing mda - mb-231 breast carcinoma xenografts . the biodegradable macromolecular agents produced more significant contrast enhancement in the tumor periphery than gd-(dtpa - bma ) . contrast enhancement in the tumor interstitium was less significant , possibly due to high interstitial fluid pressure , collapsed blood vessels forced by rapidly growing tumor tissue , and the formation of necrotic tissue in solid tumor ( padera et al 2004 ) . coronal mr images of tumor - bearing mice before ( a ) and 5 ( b ) , 15 ( c ) , 30 ( d ) , and 60 ( e ) minutes after intravenous injection of gd - dtpa cystine copolymer ( a ) , gd - dtpa cystine diethyl ester copolymer ( b ) , gd - dtpa cystamine copolymer ( c ) , and gd-(dtpa - bma ) ( d ) at a dose of 0.1 mmol - gd / kg . the polydisulfide agents provided clear visualization of the periphery and size of solid tumor , which could be useful for the evaluation of tumor response to treatment . gdcep has been studied in the noninvasive evaluation of the therapeutic response of solid tumor to an anti - vegf sirna in mice bearing mda mb-231 breast carcinoma xenografts ( wang et al 2004 ) . figure 11 shows the coronal mr images of tumor - bearing mice contrast enhanced with gdcep ( 0.1 mmol - gd / kg ) after the mice were treated for a period of 21 days with saline , a cationic polymer , anti - vegf sirna , and sirna - polymer complex . significant contrast enhancement was observed in the tumor rim of the mice , which clearly defined tumor size in the mice in different treatment groups . mice treated with the sirna and sirna - polymer complexes had much smaller tumor sizes than mice treated with saline and cationic polymers as shown by contrast - enhanced mri . contrast - enhanced coronal mr images of tumor - bearing mice with gd - dtpa cystine diethyl ester copolymer ( 0.1 mmol - gd / mmol ) after treatment with saline ( a ) , a cationic polyethyleneimine copolymer ( b ) , an anti - vegf sirna ( c ) , and a polymer  sirna complex ( d ) for 21 days . polydisulfide gd(iii ) chelates have been designed and synthesized as extracellular biodegradable macromolecular mri contrast agents . the disulfide bonds in the polymer chains can be readily cleaved by endogenous thiols into small and excretable gd(iii ) complexes . the degradability of the polydisulfides can be altered by structural modification of the agents to achieve different in vivo properties . a pharmacokinetic and biodistribution study demonstrated that gdcc has a relatively longer plasma retention time for effective contrast - enhanced mri and is rapidly excreted as low molecular - weight gd(iii ) complexes , resulting in minimal long - term gd(iii ) tissue accumulation comparable to gd(dtpa - bma ) . the structural modification of polydifulfide gd(iii ) complexes can result in biodegradable macromolecular contrast agents with various enhancement profiles in the blood pool . the polydisulfide gd(iii ) complexes have a great potential to be developed as safe , effective , biodegradable macromolecular mri contrast agents for clinical applications .
macromolecular gadolinium ( gd)(iii ) complexes have a prolonged blood circulation time and can preferentially accumulate in solid tumors , depending on the tumor blood vessel hyperpermeability , resulting in superior contrast enhancement in magnetic resonance ( mr ) cardiovascular imaging and cancer imaging as shown in animal models . 
 unfortunately , safety concerns related to these agents slow elimination from the body impede their clinical development . 
 polydisulfide gd(iii ) complexes have been designed and developed as biodegradable macromolecular magnetic resonance imaging ( mri ) contrast agents to facilitate the clearance of gd(iii ) complexes from the body after mri examinations . 
 these novel agents can act as macromolecular contrast agents for in vivo imaging and excrete rapidly as low - molecular - weight agents . the rationale and recent development of the novel biodegradable contrast agents are reviewed here . 
 polydisulfide gd(iii ) complexes have relatively long blood circulation time and gradually degrade into small gd(iii ) complexes , which are rapidly excreted via renal filtration . 
 these agents result in effective and prolonged in vivo contrast enhancement in the blood pool and tumor tissue in animal models , yet demonstrate minimal gd(iii ) tissue retention as the clinically used low - molecular - weight agents . 
 structural modification of the agents can readily alter the contrast - enhancement kinetics . 
 polydisulfide gd(iii ) complexes are promising for further clinical development as safe , effective , biodegradable macromolecular mri contrast agents for cardiovascular and cancer imaging , and for evaluation of therapeutic response .