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Nano echnology-Enabled Thienopy imidines: A F on ie in Ta ge ed D ug Deli e y
P iya A 1, *, Mahesh Kuma N 1, Shachind a L. Na gund 1, V Mu ugan 1, Sha mila A. Go e 1, Rama Mu hy 1, V
Manju Bha ga i 1, Rama Na gund 2, Sh a an L. Na gund 3, Nidhi Mal iya 3, Rama Bukka 3, Abdul Naim 3, S
Vijaya Bhaska 4, P achi Kab a 4, Ayushi Chawla 4 and Bha a h Kuma Chagale i 5
1 Depa men o Pha maceu ical Chemis y, Na gund College o Pha macy, Bengalu u-560085, India.
2 Depa men o Pha macology, Na gund College o Pha macy, Bengalu u-560085, India.
3 Depa men o Pha maceu ics, Na gund College o Pha macy, Bengalu u-560085, India.
4 Depa men o Quali y Assu ance, Na gund College o Pha macy, Bengalu u-560085, India.
5 Depa men o Pha maceu ical Chemis y, College o Pha macy, SRMIST, Ka ankula hu - 603203, India.
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Publica ion his o y: Recei ed on 25 June 2025; e ised on 23 Augus ; accep ed on 26 Augus 2025
A icle DOI: h ps://doi.o g/10.30574/wja .2025.27.2.3069
Abs ac
Thienopy imidines a e a p ominen class o he e ocyclic compounds s uc u ally ela ed o pu ines, which enables hem
o in e ac e ec i ely wi h nucleic acid-binding p o eins, kinases, and enzymes. Owing o hese in e ac ions, hey ha e
eme ged as p omising sca olds wi h wide- anging pha macological ac i i ies, including an icance , an imic obial,
an i i al, and an i-in lamma o y e ec s. Despi e hei he apeu ic ele ance, many hienopy imidine de i a i es exhibi
limi a ions such as poo aqueous solubili y, low o al bioa ailabili y, apid sys emic clea ance, and po en ial o - a ge
oxici y, which es ic hei clinical success. Recen ad ancemen s in nano echnology ha e c ea ed new oppo uni ies
o add ess hese challenges. Nanoca ie -based o mula ions, including polyme ic nanopa icles, solid lipid
nanopa icles, liposomes, dend ime s, me allic nanos uc u es, and hyb id nanosys ems, ha e demons a ed he abili y
o enhance solubili y, imp o e pha macokine ic pe o mance, and enable con olled o s imuli- esponsi e d ug elease.
Inco po a ing a ge ing ligands and mul i unc ional he agnos ic elemen s u he aligns hienopy imidine-loaded
nanopa icles wi h he g owing pa adigm o p ecision and pe sonalized medicine. In oncology, hese sys ems o e si e-
speci ic umo accumula ion and educed sys emic oxici y, while in in ec ious and in lamma o y diso de s, hey
p o ide sus ained e icacy and educed esis ance de elopmen . This e iew highligh s he mos ecen p og ess in he
design and biomedical applica ions o hienopy imidine-based nano o mula ions. I also discusses he ansla ional
challenges, including la ge-scale manu ac u ing, egula o y conside a ions, long- e m sa e y, and clinical alida ion.
Keywo ds: He e ocyclic Compounds; Nano o mula ions; P ecision Medicine; The agnos ic; Thienopy imidines
1. In oduc ion
He e ocyclic compounds ep esen a co ne s one o medicinal chemis y, accoun ing o a la ge ac ion o app o ed
d ugs and clinical candida es due o hei abili y o in e ac wi h di e se biological a ge s [1]. Among hem,
hienopy imidines (TPs) a e pa icula ly a ac i e sca olds, as hey a e s uc u al analogues o pu ines and possess
he abili y o o m hyd ogen bonds, π–π s acking, and an de Waals in e ac ions wi h nucleic acid-binding p o eins,
enzymes, and kinases [2,3].
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Figu e 1 3D-S uc u es o isome s o Thienopy imidine.
This s uc u al mimic y has been ex ensi ely exploi ed in d ug disco e y, esul ing in he de elopmen o
hienopy imidine-based inhibi o s a ge ing kinases, phosphodies e ases, and polyme ases [4]. O e he las wo
decades, TPs ha e demons a ed p omising pha macological ac i i ies ac oss mul iple he apeu ic domains. De i a i es
ha e been e alua ed o an icance [5], an imic obial [6], an i i al [7], and an i-in lamma o y p ope ies [8]. In pa icula ,
se e al kinase inhibi o s based on he TP sca old ha e en e ed ad anced p eclinical o ea ly clinical ials [9]. Despi e
hese encou aging indings, he he apeu ic applica ion o TPs has been limi ed by poo aqueous solubili y, low o al
bioa ailabili y, apid sys emic clea ance, and dose-limi ing oxici y [10,11]. These d awbacks hinde hei clinical
ansla ion and educe hei he apeu ic index. Recen ad ances in nano echnology ha e o e ed inno a i e app oaches
o o e come hese challenges. Nanoca ie sys ems such as polyme ic nanopa icles, solid lipid nanopa icles,
dend ime s, liposomes, me allic nanopa icles, and hyb id nano sys ems ha e shown he abili y o enhance solubili y,
s abili y, pha macokine ics, and si e-speci ic deli e y o small molecules [12,13]. Impo an ly, he inco po a ion o
a ge ing ligands, s imuli- esponsi e elease mechanisms, and he agnos ic ea u es has aligned nanomedicine wi h he
cu en pa adigm o p ecision and pe sonalized he apy [14]. The in eg a ion o hienopy imidines wi h nanoca ie
sys ems ep esen s an eme ging on ie in d ug deli e y esea ch. Nano o mula ions no only imp o e he
physicochemical and pha macokine ic p o ile o TPs bu also enable umo - a ge ed deli e y, con olled elease,
educed sys emic oxici y, and enhanced e icacy in p eclinical models [15,16]. Fu he mo e, nano echnology enables
combina ion he apy app oaches by co-loading TPs wi h syne gis ic d ugs, o e ing oppo uni ies o add ess mul id ug
esis ance in cance and in ec ious diseases [17].
Figu e 2 The impac o nanopa icle p ope ies on sys emic deli e y o umou s [17]
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This e iew aims o p o ide a comp ehensi e o e iew o he ecen p og ess in hienopy imidine-loaded nanoca ie s,
highligh ing ad ances in o mula ion s a egies, biological applica ions, and ansla ional challenges. I also ou lines he
u u e di ec ions o his ield, emphasizing how nano echnology can unlock he ull he apeu ic po en ial o
hienopy imidines.
2. Thienopy imidines as d ug sca olds: why o mula e nanoscale?
2.1. S uc u al Fea u es and Biological Rele ance
Thienopy imidines (TPs) a e bicyclic he e oa oma ic sca olds con aining a used hiophene and py imidine ing
sys em. Thei s uc u al simila i y o pu ines allows hem o mimic na u al nucleo ides, he eby in e ac ing wi h pu ine-
ecognizing enzymes and ecep o s [18]. This isos e ic esemblance p o ides TPs wi h high a ini y o ATP-binding si es,
which explains hei p ominence in kinase inhibi ion and nucleo ide-p ocessing enzyme modula ion [19]. The
subs i u ion pa e n on he TP co e-pa icula ly a he C2, C4, and C6 posi ions, signi ican ly modula es pha macological
ac i i y [20]. Ra ional de i a iza ion a hese si es has yielded analogues wi h po en an icance , an i i al, and an i-
in lamma o y p ope ies. Fo example, 4-amino- and 2- hioxo-de i a i es ha e shown ema kable kinase inhibi o y
ac i i y [21], while C6-subs i u ed analogues exhibi s ong an imic obial e ec s [22].
2.2. The apeu ic Po en ial and Cu en Limi a ions
The b oad-spec um ac i i y o TPs has placed hem among “p i ileged sca olds” in medicinal chemis y [23]. Se e al
de i a i es ha e ad anced in o p eclinical pipelines, including TP-based kinase inhibi o s o oncology [24] and
polyme ase inhibi o s o i al in ec ions [25]. Howe e , despi e hei p omise, TPs ace pha macokine ic and
o mula ion- ela ed challenges ha limi hei clinical ansla ion.
The majo limi a ions include:
• Low aqueous solubili y → es ic s o al abso p ion [26].
• Rapid sys emic clea ance → esul s in sho hal -li e and equen dosing [27].
• O - a ge in e ac ions and oxici y → na ow he apeu ic index [28].
• Poo umo pene a ion due o e lux pumps and physiological ba ie s [29].
These challenges unde sco e he need o o mula ion s a egies ha imp o e solubili y, enhance bioa ailabili y,
p olong sys emic ci cula ion, and enable si e-speci ic deli e y.
2.3. Ra ionale o Nano echnology In eg a ion
Nanoca ie sys ems ha e eme ged as ans o ma i e ools o add ess he abo e sho comings. By encapsula ing TPs in
nanoscale ca ie s, se e al ad an ages can be achie ed [30]:
• Enhanced solubili y and s abili y o poo ly wa e -soluble analogues.
• Con olled and sus ained elease, p e en ing apid clea ance.
• Passi e a ge ing ia he enhanced pe meabili y and e en ion (EPR) e ec in umo s.
• Ac i e a ge ing h ough unc ionaliza ion wi h ligands (an ibodies, pep ides, ap ame s).
• Reduced sys emic oxici y, owing o localized deli e y and lowe o - a ge accumula ion.
• The agnos ic po en ial, when combined wi h imaging agen s o s imuli- esponsi e elease igge s.
2.4. Case o Nano-Thienopy imidines
In p eclinical models, nano o mula ions o TPs ha e demons a ed imp o ed pha macokine ics and he apeu ic
ou comes compa ed o ee d ugs. Fo example, liposomal hienopy imidine de i a i es exhibi ed p olonged ci cula ion
and supe io an icance e icacy [31]. Simila ly, polyme ic nanopa icles ha e been used o co-deli e TPs wi h PI3K
inhibi o s, showing syne gis ic an i umo ac i i y [32]. These indings highligh he ansla ional po en ial o
nano echnology-enabled TPs as nex -gene a ion he apeu ics.
3. Nanoca ie pla o ms o hienopy imidines
Nanoca ie sys ems ep esen e sa ile pla o ms capable o add essing he solubili y, s abili y, and bioa ailabili y
challenges o hienopy imidines (TPs). Depending on hei composi ion, su ace chemis y, and physicochemical
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p ope ies, nanoca ie s can be ailo ed o passi e a ge ing, ac i e a ge ing, con olled elease, and he agnos ic
applica ions. Below, he mos ele an sys ems a e discussed wi h emphasis on hei applicabili y o TP-based
he apeu ics.
3.1. Polyme ic Nanopa icles
Polyme ic nanopa icles (PNPs) a e among he mos widely s udied ca ie s o poo ly soluble small molecules. They
a e composed o na u al o syn he ic polyme s such as PLGA (poly (lac ic-co-glycolic acid)), PLA (polylac ic acid), PEG
(polye hylene glycol), and chi osan [33].
• Ad an ages: Biodeg adabili y, con olled elease kine ics, abili y o be su ace- unc ionalized wi h a ge ing
ligands.
• Applica ions o TPs: PNPs can encapsula e hyd ophobic TP de i a i es, enhancing solubili y and ci cula ion
hal -li e. In a ecen s udy, a TP-kinase inhibi o encapsula ed in PLGA-PEG nanopa icles showed highe umo
accumula ion and s onge g ow h inhibi ion compa ed o i s ee o m [34].
• Eme ging s a egies: S imuli- esponsi e PNPs (pH- o edox-sensi i e) ha e been designed o elease TPs
speci ically in he umo mic oen i onmen , imp o ing he apeu ic index [35].
Figu e 3 Types o s uc u al o ms o polyme ic nanopa icles [67]
3.2. Liposomes
Liposomes a e phospholipid bilaye esicles capable o en apping bo h hyd ophilic and hyd ophobic d ugs. They
emain he mos clinically success ul nanoca ie s, wi h se e al liposomal d ugs app o ed by he FDA [36].
• Ad an ages: Biocompa ibili y, capaci y o high d ug loading, long-ci cula ing s eal h o mula ions ia
PEGyla ion.
• Applica ions o TPs: Liposomal deli e y o hienopy imidine analogues has been shown o ex end plasma hal -
li e, imp o e umo up ake, and educe sys emic oxici y [37].
• The agnos ic po en ial: Inco po a ion o luo escen o MRI con as agen s in o TP-liposomes enables
simul aneous he apy and imaging [38].
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Figu e 4 Schema ic ep esen a ion o he di e en ypes o liposomal d ug deli e y sys ems [68]
3.3. Solid Lipid Nanopa icles (SLNs) and Nanos uc u ed Lipid Ca ie s (NLCs)
Solid Lipid Nanopa icles a e colloidal ca ie s composed o physiological lipids ha emain solid a bo h oom and
body empe a u e. They we e i s de eloped in he 1990s as an al e na i e o adi ional d ug deli e y sys ems such
as emulsions, liposomes, and polyme ic nanopa icles. SLNs combine he ad an ages o hese ca ie s, including
biocompa ibili y, con olled d ug elease, and p o ec ion o labile molecules om chemical deg ada ion. Typically, SLNs
a e p epa ed using lipids like iglyce ides, a y acids, waxes, o glyce ide mix u es s abilized wi h su ac an s. The
solid lipid co e p o ides a igid ma ix ha can encapsula e bo h hyd ophilic and lipophilic d ugs. Owing o hei small
size (50–1000 nm), SLNs enhance d ug solubili y, imp o e bioa ailabili y, and enable si e-speci ic a ge ing. Howe e ,
one majo limi a ion o SLNs is hei ela i ely low d ug-loading capaci y and he isk o d ug expulsion du ing s o age
due o high c ys allini y o he lipid ma ix. Despi e his, SLNs emain widely s udied o applica ions in o al, opical,
ocula , pulmona y, and pa en e al d ug deli e y. Nanos uc u ed Lipid Ca ie s we e de eloped as he “second
gene a ion” o lipid nanopa icles o o e come he d awbacks o SLNs. Unlike SLNs, which a e composed solely o solid
lipids, NLCs inco po a e a mix u e o solid lipids and liquid lipids (oils). This combina ion c ea es an impe ec lipid
ma ix wi h mo e ee space o d ug molecules, esul ing in highe d ug-loading capaci y and educed d ug expulsion
du ing s o age.
NLCs a e classi ied in o h ee ypes based on s uc u al a angemen :
• Impe ec ype – o med by mixing solid lipids wi h spa ially di e en liquid lipids o gene a e s uc u al
impe ec ions.
• Mul iple ype – con aining nano compa men s o oil dis ibu ed wi hin he solid lipid ma ix.
• Amo phous ype – o med using special lipids ha p e en c ys alliza ion, main aining he lipid ma ix in a
less o de ed s a e.
The p esence o bo h solid and liquid lipids in NLCs p o ides lexibili y in o mula ion design, con olled elease
beha iou , and imp o ed s abili y compa ed o SLNs. NLCs ha e demons a ed signi ican po en ial in he deli e y o
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poo ly soluble d ugs, pep ides, p o eins, nucleic acids, and cosme ic ac i es. They a e also explo ed o cance he apy,
b ain a ge ing, and accine deli e y due o hei abili y o enhance pe meabili y ac oss biological ba ie s.
SLNs and NLCs a e composed o solid o mixed lipid ma ices s abilized by su ac an s. They p o ide highe physical
s abili y and con olled elease compa ed o con en ional liposomes [39].
• Ad an ages: Biodeg adable lipids, scalable p oduc ion, sui abili y o o al deli e y.
• Applica ions o TPs: Encapsula ion o poo ly soluble TP de i a i es in SLNs has demons a ed imp o ed o al
abso p ion and enhanced an icance e icacy in xenog a models [40].
Figu e 5 Schema ic ep esen a ion o he di e en ypes o SLNs AND NLCs [69]
3.4. Dend ime s
Dend ime s a e a unique class o syn he ic mac omolecules cha ac e ized by hei highly b anched, ee-like s uc u e.
The e m “dend ime ” comes om he G eek wo ds dend on ( ee) and me os (pa ), e lec ing hei b anching
a chi ec u e. These nanoscale, h ee-dimensional polyme s a e buil a ound a cen al co e, wi h epea ing laye s (called
gene a ions) o b anching uni s ex ending ou wa d o e minal unc ional g oups. The well-de ined s uc u e o
dend ime s p o ides hem wi h dis inc p ope ies such as uni o m size, high su ace unc ionali y, and he abili y o
encapsula e o a ach gues molecules. Thei nanoscale dimensions (1–10 nm) and mul i alency make hem highly
sui able o biomedical and pha maceu ical applica ions.
Dend ime s a e highly b anched, ee-like polyme s wi h unc ional end g oups ha enable p ecise d ug conjuga ion
and mul i alency [41].
• Ad an ages: High d ug-loading capaci y, unable su ace chemis y, po en ial o gene-d ug co-deli e y.
• Applica ions o TPs: Amino- e mina ed PAMAM dend ime s ha e been used o conjuga e hienopy imidine
analogues, yielding wa e -soluble complexes wi h enhanced cy o oxici y agains esis an cance cell lines [42].
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Figu e 6 Di e en ypes o dend ime s [70]
3.5. Ino ganic and Hyb id Nanopa icles
Ino ganic ca ie s such as gold nanopa icles, i on oxide nanopa icles, and mesopo ous silica a e a ac i e o hei
he agnos ic capabili ies [43].
• Ad an ages: In insic imaging ea u es (e.g., MRI, CT), pho o he mal o pho odynamic p ope ies.
• Applica ions o TPs: Mesopo ous silica nanopa icles loaded wi h TP-kinase inhibi o s ha e demons a ed
con olled elease and e ec i e umo a ge ing [44]. Hyb id lipid–polyme ca ie s a e also gaining in e es ,
o e ing he s abili y o polyme s wi h he biocompa ibili y o lipids [45].
3.6. Exosomes and Biomime ic Nanoca ie s
Exosomes and cell memb ane–coa ed nanopa icles ep esen he nex gene a ion o d ug deli e y sys ems due o hei
abili y o e ade immune clea ance and achie e homo ypic a ge ing [46].
Po en ial o TPs: TP-loaded exosomes de i ed om umo cells may p o ide “T ojan ho se” deli e y, enhance umo
selec i i y while educe immunogenici y [47]. Though s ill in p eclinical s ages, biomime ic deli e y o e s a highly
p omising a enue o TP he apeu ics.
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4. Ta ge ing and elease s a egies
E ec i e nanopa icle-enabled deli e y o hienopy imidines (TPs) depends no only on he ca ie ma e ial bu also on
how and when he payload is eleased and whe he he ca ie can selec i ely accumula e in he diseased issue. Mode n
nano o mula ion design, he e o e, blends passi e and ac i e a ge ing p inciples wi h enginee ed elease igge s o
maximize on- a ge exposu e while minimizing sys emic oxici y.
4.1. Passi e a ge ing: exploi ing physiology
Passi e a ge ing le e ages he pa hophysiological ea u es o diseased issues, mos p ominen ly he enhanced
pe meabili y and e en ion (EPR) e ec in solid umo s, o concen a e nanopa icles a he disease si e [13].
Nanopa icles sized oughly 50-200 nm wi h neu al- o-sligh ly-nega i e su ace cha ge end o ex a asa e h ough
leaky umo ascula u e and be e ained due o poo lympha ic d ainage, inc easing local d ug AUC and he apeu ic
index [13,29]. Fo TPs, which a e o en hyd ophobic and apidly clea ed when gi en as a ee d ug, encapsula ion in
app op ia ely sized liposomes o polyme ic pa icles imp o es in a umo al exposu e and educes o - a ge
dis ibu ion [25,34]. Howe e , EPR is he e ogeneous be ween umo s and pa ien s; clinical ansla ion equi es ca e ul
pa icle sizing, su ace enginee ing (e.g., PEGyla ion), and companion diagnos ics o iden i y likely EPR- esponsi e
umo s [13,31].
4.2. Ac i e a ge ing: ecep o -media ed deli e y
Ac i e a ge ing augmen s passi e accumula ion by deco a ing nanopa icle su aces wi h ligands ha bind ecep o s
o e exp essed on a ge cells, p omo ing cellula up ake and in acellula deli e y [32]. Common ligands used in TP nano
o mula ions include small molecules ( ola e), pep ides (RGD), an ibodies o an ibody agmen s (an i-EGFR, HER2),
and ap ame s [32–35]. Fo example, ola e-conjuga ed PLGA nanopa icles ca ying a TP CDK inhibi o achie ed highe
up ake and cy o oxici y in ola e ecep o –posi i e cell lines e sus non- a ge ed con ols [35].
4.3. S imuli- esponsi e elease: iming he payload
Con olled elease mechanisms enable nanopa icles o hold TPs s ably in ci cula ion and discha ge hem selec i ely in
he umo mic oen i onmen o wi hin a ge cells. S imuli- esponsi e s a egies a e b oadly classi ied in o in e nal
igge s (pH, edox, enzymes) and ex e nal igge s ( empe a u e, ul asound, magne ic ield, ligh ).
• pH- esponsi e sys ems: Tumo in e s i ium and endosomes a e mo e acidic han blood; acid-labile linke s
(hyd azones, cis-aconi yl, ace al bonds) o ma e ials ha swell/ionize unde acidic pH elease d ug
p e e en ially a he a ge si e, enhancing in acellula TP concen a ion while spa ing no mal issue [36,37].
• Redox-sensi i e sys ems: Ele a ed in acellula glu a hione (GSH) le els in cance cells can clea e disul ide
bonds inco po a ed in o nanopa icle ma ices o linke s, igge ing elease o TP payloads selec i ely inside
umo cells [36,38].
• Enzyme- esponsi e sys ems: P o ease-sensi i e linke s (MMP, ca hepsin) espond o umo -o e exp essed
enzymes, enabling local elease; his is use ul whe e pH di e ences a e modes [36].
• Ex e nally applied igge s: Mild hype he mia, ocused ul asound, ligh (nea -in a ed), o al e na ing
magne ic ields pe mi spa io empo al con ol o e elease. The mo-sensi i e liposomes o magne o-
esponsi e ca ie s can be used o ‘uncage’ TPs a a umo si e du ing a ea men session, p o iding on-demand
deli e y o po en bu oxic agen s [17,18].
Success ul implemen a ion o s imuli- esponsi e elease equi es balancing ci cula o y s abili y ( o a oid p ema u e
elease) wi h apid esponsi eness a he a ge . Fo TPs wi h na ow he apeu ic windows, such igge s a e
pa icula ly aluable o educe sys emic exposu e while achie ing high in a umo al concen a ions.
4.4. Combina ion s a egies and co-deli e y
Resis ance o single-agen he apy is common in kinase-d i en cance s. Nanoca ie s easily accommoda e co-loading o
TPs wi h complemen a y he apeu ics (chemo he apy, siRNA, immune modula o s) o achie e syne gis ic e ec s and
block escape pa hways. Co-deli e y can synch onize pha macokine ics and ensu e bo h agen s each he same cells a
he apeu ic a ios, some hing di icul o achie e wi h sepa a e adminis a ions [17,40]. Examples include TP PI3K
inhibi o s co- o mula ed wi h axanes o o e come mic o ubule- a ge ed d ug esis ance, o TP + siRNA cons uc s ha
silence esis ance media o s while inhibi ing kinase signalling. Design challenges o co-deli e y include di e en ial
solubili y (hyd ophilic s hyd ophobic ca go), elease kine ics (ma ched s s aged elease), and physicochemical
compa ibili y. Laye ed a chi ec u es o co e-shell o ma s can sepa a e payloads and une elease p o iles acco dingly.
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4.5. In acellula a icking and endosomal escape
Fo many TP a ge s (e.g., in acellula kinases), success ul he apy equi es deli e y o ac i e d ug in o he cy osol o
nucleus. A e ecep o -media ed endocy osis, nanopa icles mus a e se he endosomal pa hway; endosomal
en apmen leads o lysosomal deg ada ion o slow elease. S a egies o p omo e endosomal escape-p o on sponge
e ec (ca ionic polyme s), usogenic pep ides, and pH- esponsi e memb ane-dis up ing moie ies a e he e o e in eg al
o he design [35,36]. Ca e ul selec ion o hese ea u es imp o es in acellula bioa ailabili y o TPs and can ma kedly
enhance po ency while allowing lowe dosing.
4.6. Imaging-guided a ge ing ( he agnos ic)
Combining imaging p obes wi h TP nano o mula ions enables non-in asi e moni o ing o biodis ibu ion, a ge
engagemen , and he apeu ic esponse. Co-encapsula ed luo opho es, adiolabels, o MRI con as agen s p o ide
PK/PD eadou s ha can in o m dosing and pa ien selec ion, enhancing clinical ansla ion [17,39]. The agnos ic TP
sys ems a e pa icula ly a ac i e in ea ly-phase ials o s a i y esponde s and op imize schedules.
4.6.1. P ac ical akeaways o TP nano o mula ion design
• S a wi h passi e a ge ing (op imize size, PDI, and s eal h) and laye ac i e a ge ing only when a alida ed
ecep o is a ailable.
• Use s imuli- esponsi e elease o con ine exposu e when TPs ha e na ow he apeu ic windows.
• Fo combina ion he apy, design ma ched elease kine ics o s aged deli e y using modula a chi ec u es.
• Inco po a e endosomal escape ea u es when in acellula deli e y is equi ed.
• Conside he agnos ic elemen s o de- isk ansla ion ia imaging-based pa ien selec ion and PK acking [40].
5. Case s udies o hienopy imidine-loaded nanopa icles
While hienopy imidines (TPs) ha e been well ecognized as po en kinase inhibi o s and an imic obial sca olds, hei
di ec clinical applica ion has been limi ed due o solubili y, me abolic ins abili y, and sys emic oxici y. The
inco po a ion o TPs in o nanoca ie pla o ms has been explo ed in mul iple p eclinical s udies o o e come hese
ba ie s. Below, selec ed case s udies illus a e he design, pe o mance, and he apeu ic po en ial o nano-
hienopy imidines.
5.1. Liposomal o mula ions o TP kinase inhibi o s
One o he ea lies app oaches in ol ed liposomal encapsula ion o TP-based kinase inhibi o s o imp o e hei
pha macokine ics. In a s udy by El-Sayed e al., liposomes loaded wi h a 2- hioxo- hieno[2,3-d] py imidine de i a i e
demons a ed enhanced plasma s abili y and supe io cy o oxici y agains b eas cance cells compa ed o he ee d ug
[41]. The liposomal sys em imp o ed solubili y and acili a ed passi e accumula ion in umo issues ia he EPR e ec .
Impo an ly, in i o umo g ow h inhibi ion was signi ican ly highe in he liposomal g oup, unde sco ing he clinical
po en ial o lipid-based ca ie s.
5.2. Polyme ic nanopa icles o con olled deli e y
Polyme ic nanopa icles (PNPs), pa icula ly hose ab ica ed om PLGA and PEG-PLGA copolyme s, ha e been
employed o deli e poo ly soluble TP analogues. A TP-de i ed PI3K inhibi o encapsula ed in PLGA nanopa icles
showed sus ained elease o e 72 h and signi ican ly p olonged plasma hal -li e in oden models [42]. When es ed in
xenog a umo s, PNPs achie ed supe io umo g ow h supp ession and educed sys emic oxici y compa ed o ee
d ug adminis a ion. Ta ge ed o mula ions using ola e-modi ied PLGA u he inc eased up ake in ola e ecep o -
posi i e cance s [35].
5.3. Solid lipid nanopa icles (SLNs) o o al deli e y
Gi en he poo o al bioa ailabili y o many TP analogs, SLNs ha e been de eloped o imp o e gas oin es inal
abso p ion. A TP-based an i ungal compound o mula ed in o SLNs exhibi ed mo e han a h ee old inc ease in o al
bioa ailabili y in a models ela i e o he ee compound [43]. Enhanced lympha ic anspo and imp o ed mucosal
pe meabili y con ibu ed o be e sys emic exposu e. Such s a egies a e a ac i e o ch onic condi ions equi ing
o al adminis a ion and sus ained he apeu ic le els.
Wo ld Jou nal o Ad anced Resea ch and Re iews, 2025, 27(02), 1858-1873
1873
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