Nanotechnology-Enabled Thienopyrimidines: A Frontier in Targeted Drug Delivery

 Corresponding author: Priya A Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Nanotechnology-Enabled Thienopyrimidines: A Frontier in Targeted Drug Delivery Priya A 1, *, Mahesh Kumar N 1, Shachindra L. Nargund 1, V Murugan 1, Sharmila A. Gote 1, Rama Murthy 1, V Manju Bhargavi 1, Rama Nargund 2, Shravan L. Nargund 3, Nidhi Malviya 3, Rama Bukka 3, Abdul Naim 3, S Vijaya Bhaskar 4, Prachi Kabra 4, Ayushi Chawla 4 and Bharath Kumar Chagaleti 5 1 Department of Pharmaceutical Chemistry, Nargund College of Pharmacy, Bengaluru-560085, India. 2 Department of Pharmacology, Nargund College of Pharmacy, Bengaluru-560085, India. 3 Department of Pharmaceutics, Nargund College of Pharmacy, Bengaluru-560085, India. 4 Department of Quality Assurance, Nargund College of Pharmacy, Bengaluru-560085, India. 5 Department of Pharmaceutical Chemistry, College of Pharmacy, SRMIST, Kattankulathur603203, India. World Journal of Advanced Research and Reviews, 2025, 27(02), 1858-1873 Publication history: Received on 25 June 2025; revised on 23 August; accepted on 26 August 2025 Article DOI: https://doi.org/10.30574/wjarr.2025.27.2.3069 Abstract Thienopyrimidines are a prominent class of heterocyclic compounds structurally related to purines, which enables them to interact effectively with nucleic acid-binding proteins, kinases, and enzymes. Owing to these interactions, they have emerged as promising scaffolds with wide-ranging pharmacological activities, including anticancer, antimicrobial, antiviral, and anti-inflammatory effects. Despite their therapeutic relevance, many thienopyrimidine derivatives exhibit limitations such as poor aqueous solubility, low oral bioavailability, rapid systemic clearance, and potential off-target toxicity, which restrict their clinical success. Recent advancements in nanotechnology have created new opportunities to address these challenges. Nanocarrier-based formulations, including polymeric nanoparticles, solid lipid nanoparticles, liposomes, dendrimers, metallic nanostructures, and hybrid nanosystems, have demonstrated the ability to enhance solubility, improve pharmacokinetic performance, and enable controlled or stimuli-responsive drug release. Incorporating targeting ligands and multifunctional theragnostic elements further aligns thienopyrimidine-loaded nanoparticles with the growing paradigm of precision and personalized medicine. In oncology, these systems offer sitespecific tumor accumulation and reduced systemic toxicity, while in infectious and inflammatory disorders, they provide sustained efficacy and reduced resistance development. This review highlights the most recent progress in the design and biomedical applications of thienopyrimidine-based nano formulations. It also discusses the translational challenges, including large-scale manufacturing, regulatory considerations, long-term safety, and clinical validation. Keywords: Heterocyclic Compounds; Nanoformulations; Precision Medicine; Theragnostic; Thienopyrimidines 1. Introduction Heterocyclic compounds represent a cornerstone of medicinal chemistry, accounting for a large fraction of approved drugs and clinical candidates due to their ability to interact with diverse biological targets [1]. Among them, thienopyrimidines (TPs) are particularly attractive scaffolds, as they are structural analogues of purines and possess the ability to form hydrogen bonds, π–π stacking, and van der Waals interactions with nucleic acid-binding proteins, enzymes, and kinases [2,3]. World Journal of Advanced Research and Reviews, 2025, 27(02), 1858-1873 1859 Figure 1 3D-Structures of isomers of Thienopyrimidine. This structural mimicry has been extensively exploited in drug discovery, resulting in the development of thienopyrimidine-based inhibitors targeting kinases, phosphodiesterases, and polymerases [4]. Over the last two decades, TPs have demonstrated promising pharmacological activities across multiple therapeutic domains. Derivatives have been evaluated for anticancer [5], antimicrobial [6], antiviral [7], and anti-inflammatory properties [8]. In particular, several kinase inhibitors based on the TP scaffold have entered advanced preclinical or early clinical trials [9]. Despite these encouraging findings, the therapeutic application of TPs has been limited by poor aqueous solubility, low oral bioavailability, rapid systemic clearance, and dose-limiting toxicity [10,11]. These drawbacks hinder their clinical translation and reduce their therapeutic index. Recent advances in nanotechnology have offered innovative approaches to overcome these challenges. Nanocarrier systems such as polymeric nanoparticles, solid lipid nanoparticles, dendrimers, liposomes, metallic nanoparticles, and hybrid nano systems have shown the ability to enhance solubility, stability, pharmacokinetics, and site-specific delivery of small molecules [12,13]. Importantly, the incorporation of targeting ligands, stimuli-responsive release mechanisms, and theragnostic features has aligned nanomedicine with the current paradigm of precision and personalized therapy [14]. The integration of thienopyrimidines with nanocarrier systems represents an emerging frontier in drug delivery research. Nanoformulations not only improve the physicochemical and pharmacokinetic profile of TPs but also enable tumor-targeted delivery, controlled release, reduced systemic toxicity, and enhanced efficacy in preclinical models [15,16]. Furthermore, nanotechnology enables combination therapy approaches by co-loading TPs with synergistic drugs, offering opportunities to address multidrug resistance in cancer and infectious diseases [17]. Figure 2 The impact of nanoparticle properties on systemic delivery to tumours [17] World Journal of Advanced Research and Reviews, 2025, 27(02), 1858-1873 1860 This review aims to provide a comprehensive overview of the recent progress in thienopyrimidine-loaded nanocarriers, highlighting advances in formulation strategies, biological applications, and translational challenges. It also outlines the future directions of this field, emphasizing how nanotechnology can unlock the full therapeutic potential of thienopyrimidines. 2. Thienopyrimidines as drug scaffolds: why formulate nanoscale? 2.1. Structural Features and Biological Relevance Thienopyrimidines (TPs) are bicyclic heteroaromatic scaffolds containing a fused thiophene and pyrimidine ring system. Their structural similarity to purines allows them to mimic natural nucleotides, thereby interacting with purinerecognizing enzymes and receptors [18]. This isosteric resemblance provides TPs with high affinity for ATP-binding sites, which explains their prominence in kinase inhibition and nucleotide-processing enzyme modulation [19]. The substitution pattern on the TP core-particularly at the C2, C4, and C6 positions, significantly modulates pharmacological activity [20]. Rational derivatization at these sites has yielded analogues with potent anticancer, antiviral, and antiinflammatory properties. For example, 4-aminoand 2-thioxo-derivatives have shown remarkable kinase inhibitory activity [21], while C6-substituted analogues exhibit strong antimicrobial effects [22]. 2.2. Therapeutic Potential and Current Limitations The broad-spectrum activity of TPs has placed them among “privileged scaffolds” in medicinal chemistry [23]. Several derivatives have advanced into preclinical pipelines, including TP-based kinase inhibitors for oncology [24] and polymerase inhibitors for viral infections [25]. However, despite their promise, TPs face pharmacokinetic and formulation-related challenges that limit their clinical translation. The major limitations include: • Low aqueous solubility → restricts oral absorption [26]. • Rapid systemic clearance → results in short half-life and frequent dosing [27]. • Off-target interactions and toxicity → narrow therapeutic index [28]. • Poor tumor penetration due to efflux pumps and physiological barriers [29]. These challenges underscore the need for formulation strategies that improve solubility, enhance bioavailability, prolong systemic circulation, and enable site-specific delivery. 2.3. Rationale for Nanotechnology Integration Nanocarrier systems have emerged as transformative tools to address the above shortcomings. By encapsulating TPs in nanoscale carriers, several advantages can be achieved [30]: • Enhanced solubility and stability of poorly water-soluble analogues. • Controlled and sustained release, preventing rapid clearance. • Passive targeting via the enhanced permeability and retention (EPR) effect in tumors. • Active targeting through functionalization with ligands (antibodies, peptides, aptamers). • Reduced systemic toxicity, owing to localized delivery and lower off-target accumulation. • Theragnostic potential, when combined with imaging agents or stimuli-responsive release triggers. 2.4. Case for Nano-Thienopyrimidines In preclinical models, nano formulations of TPs have demonstrated improved pharmacokinetics and therapeutic outcomes compared to free drugs. For example, liposomal thienopyrimidine derivatives exhibited prolonged circulation and superior anticancer efficacy [31]. Similarly, polymeric nanoparticles have been used to co-deliver TPs with PI3K inhibitors, showing synergistic antitumor activity [32]. These findings highlight the translational potential of nanotechnology-enabled TPs as next-generation therapeutics. 3. Nanocarrier platforms for thienopyrimidines Nanocarrier systems represent versatile platforms capable of addressing the solubility, stability, and bioavailability challenges of thienopyrimidines (TPs). Depending on their composition, surface chemistry, and physicochemical World Journal of Advanced Research and Reviews, 2025, 27(02), 1858-1873 1861 properties, nanocarriers can be tailored for passive targeting, active targeting, controlled release, and theragnostic applications. Below, the most relevant systems are discussed with emphasis on their applicability to TP-based therapeutics. 3.1. Polymeric Nanoparticles Polymeric nanoparticles (PNPs) are among the most widely studied carriers for poorly soluble small molecules. They are composed of natural or synthetic polymers such as PLGA (poly (lactic-co-glycolic acid)), PLA (polylactic acid), PEG (polyethylene glycol), and chitosan [33]. • Advantages: Biodegradability, controlled release kinetics, ability to be surface-functionalized with targeting ligands. • Applications to TPs: PNPs can encapsulate hydrophobic TP derivatives, enhancing solubility and circulation half-life. In a recent study, a TP-kinase inhibitor encapsulated in PLGA-PEG nanoparticles showed higher tumor accumulation and stronger growth inhibition compared to its free form [34]. • Emerging strategies: Stimuli-responsive PNPs (pHor redox-sensitive) have been designed to release TPs specifically in the tumor microenvironment, improving therapeutic index [35]. Figure 3 Types of structural forms of polymeric nanoparticles [67] 3.2. Liposomes Liposomes are phospholipid bilayer vesicles capable of entrapping both hydrophilic and hydrophobic drugs. They remain the most clinically successful nanocarriers, with several liposomal drugs approved by the FDA [36]. • Advantages: Biocompatibility, capacity for high drug loading, long-circulating stealth formulations via PEGylation. • Applications to TPs: Liposomal delivery of thienopyrimidine analogues has been shown to extend plasma halflife, improve tumor uptake, and reduce systemic toxicity [37]. • Theragnostic potential: Incorporation of fluorescent or MRI contrast agents into TP-liposomes enables simultaneous therapy and imaging [38]. World Journal of Advanced Research and Reviews, 2025, 27(02), 1858-1873 1862 Figure 4 Schematic representation of the different types of liposomal drug delivery systems [68] 3.3. Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs) Solid Lipid Nanoparticles are colloidal carriers composed of physiological lipids that remain solid at both room and body temperature. They were first developed in the 1990s as an alternative to traditional drug delivery systems such as emulsions, liposomes, and polymeric nanoparticles. SLNs combine the advantages of these carriers, including biocompatibility, controlled drug release, and protection of labile molecules from chemical degradation. Typically, SLNs are prepared using lipids like triglycerides, fatty acids, waxes, or glyceride mixtures stabilized with surfactants. The solid lipid core provides a rigid matrix that can encapsulate both hydrophilic and lipophilic drugs. Owing to their small size (50–1000 nm), SLNs enhance drug solubility, improve bioavailability, and enable site-specific targeting. However, one major limitation of SLNs is their relatively low drug-loading capacity and the risk of drug expulsion during storage due to high crystallinity of the lipid matrix. Despite this, SLNs remain widely studied for applications in oral, topical, ocular, pulmonary, and parenteral drug delivery. Nanostructured Lipid Carriers were developed as the “second generation” of lipid nanoparticles to overcome the drawbacks of SLNs. Unlike SLNs, which are composed solely of solid lipids, NLCs incorporate a mixture of solid lipids and liquid lipids (oils). This combination creates an imperfect lipid matrix with more free space for drug molecules, resulting in higher drug-loading capacity and reduced drug expulsion during storage. NLCs are classified into three types based on structural arrangement: • Imperfect type – formed by mixing solid lipids with spatially different liquid lipids to generate structural imperfections. • Multiple type – containing nano compartments of oil distributed within the solid lipid matrix. • Amorphous type – formed using special lipids that prevent crystallization, maintaining the lipid matrix in a less ordered state. The presence of both solid and liquid lipids in NLCs provides flexibility in formulation design, controlled release behaviour, and improved stability compared to SLNs. NLCs have demonstrated significant potential in the delivery of World Journal of Advanced Research and Reviews, 2025, 27(02), 1858-1873 1863 poorly soluble drugs, peptides, proteins, nucleic acids, and cosmetic actives. They are also explored for cancer therapy, brain targeting, and vaccine delivery due to their ability to enhance permeability across biological barriers. SLNs and NLCs are composed of solid or mixed lipid matrices stabilized by surfactants. They provide higher physical stability and controlled release compared to conventional liposomes [39]. • Advantages: Biodegradable lipids, scalable production, suitability for oral delivery. • Applications to TPs: Encapsulation of poorly soluble TP derivatives in SLNs has demonstrated improved oral absorption and enhanced anticancer efficacy in xenograft models [40]. Figure 5 Schematic representation of the different types of SLNs AND NLCs [69] 3.4. Dendrimers Dendrimers are a unique class of synthetic macromolecules characterized by their highly branched, tree-like structure. The term “dendrimer” comes from the Greek words dendron (tree) and meros (part), reflecting their branching architecture. These nanoscale, three-dimensional polymers are built around a central core, with repeating layers (called generations) of branching units extending outward to terminal functional groups. The well-defined structure of dendrimers provides them with distinct properties such as uniform size, high surface functionality, and the ability to encapsulate or attach guest molecules. Their nanoscale dimensions (1–10 nm) and multivalency make them highly suitable for biomedical and pharmaceutical applications. Dendrimers are highly branched, tree-like polymers with functional end groups that enable precise drug conjugation and multivalency [41]. • Advantages: High drug-loading capacity, tunable surface chemistry, potential for gene-drug co-delivery. • Applications to TPs: Amino-terminated PAMAM dendrimers have been used to conjugate thienopyrimidine analogues, yielding water-soluble complexes with enhanced cytotoxicity against resistant cancer cell lines [42]. World Journal of Advanced Research and Reviews, 2025, 27(02), 1858-1873 1864 Figure 6 Different types of dendrimers [70] 3.5. Inorganic and Hybrid Nanoparticles Inorganic carriers such as gold nanoparticles, iron oxide nanoparticles, and mesoporous silica are attractive for their theragnostic capabilities [43]. • Advantages: Intrinsic imaging features (e.g., MRI, CT), photothermal or photodynamic properties. • Applications to TPs: Mesoporous silica nanoparticles loaded with TP-kinase inhibitors have demonstrated controlled release and effective tumor targeting [44]. Hybrid lipid–polymer carriers are also gaining interest, offering the stability of polymers with the biocompatibility of lipids [45]. 3.6. Exosomes and Biomimetic Nanocarriers Exosomes and cell membrane–coated nanoparticles represent the next generation of drug delivery systems due to their ability to evade immune clearance and achieve homotypic targeting [46]. Potential for TPs: TP-loaded exosomes derived from tumor cells may provide “Trojan horse” delivery, enhance tumor selectivity while reduce immunogenicity [47]. Though still in preclinical stages, biomimetic delivery offers a highly promising avenue for TP therapeutics. World Journal of Advanced Research and Reviews, 2025, 27(02), 1858-1873 1865 4. Targeting and release strategies Effective nanoparticle-enabled delivery of thienopyrimidines (TPs) depends not only on the carrier material but also on how and when the payload is released and whether the carrier can selectively accumulate in the diseased tissue. Modern nano formulation design, therefore, blends passive and active targeting principles with engineered release triggers to maximize on-target exposure while minimizing systemic toxicity. 4.1. Passive targeting: exploiting physiology Passive targeting leverages the pathophysiological features of diseased tissues, most prominently the enhanced permeability and retention (EPR) effect in solid tumors, to concentrate nanoparticles at the disease site [13]. Nanoparticles sized roughly 50-200 nm with neutral-to-slightly-negative surface charge tend to extravasate through leaky tumor vasculature and be retained due to poor lymphatic drainage, increasing local drug AUC and therapeutic index [13,29]. For TPs, which are often hydrophobic and rapidly cleared when given as a free drug, encapsulation in appropriately sized liposomes or polymeric particles improves intratumoral exposure and reduces off-target distribution [25,34]. However, EPR is heterogeneous between tumors and patients; clinical translation requires careful particle sizing, surface engineering (e.g., PEGylation), and companion diagnostics to identify likely EPR-responsive tumors [13,31]. 4.2. Active targeting: receptor-mediated delivery Active targeting augments passive accumulation by decorating nanoparticle surfaces with ligands that bind receptors overexpressed on target cells, promoting cellular uptake and intracellular delivery [32]. Common ligands used in TP nano formulations include small molecules (folate), peptides (RGD), antibodies or antibody fragments (anti-EGFR, HER2), and aptamers [32–35]. For example, folate-conjugated PLGA nanoparticles carrying a TP CDK inhibitor achieved higher uptake and cytotoxicity in folate receptor–positive cell lines versus non-targeted controls [35]. 4.3. Stimuli-responsive release: timing the payload Controlled release mechanisms enable nanoparticles to hold TPs stably in circulation and discharge them selectively in the tumor microenvironment or within target cells. Stimuli-responsive strategies are broadly classified into internal triggers (pH, redox, enzymes) and external triggers (temperature, ultrasound, magnetic field, light). • pH-responsive systems: Tumor interstitium and endosomes are more acidic than blood; acid-labile linkers (hydrazones, cis-aconityl, acetal bonds) or materials that swell/ionize under acidic pH release drug preferentially at the target site, enhancing intracellular TP concentration while sparing normal tissue [36,37]. • Redox-sensitive systems: Elevated intracellular glutathione (GSH) levels in cancer cells can cleave disulfide bonds incorporated into nanoparticle matrices or linkers, triggering release of TP payloads selectively inside tumor cells [36,38]. • Enzyme-responsive systems: Protease-sensitive linkers (MMP, cathepsin) respond to tumor-overexpressed enzymes, enabling local release; this is useful where pH differences are modest [36]. • Externally applied triggers: Mild hyperthermia, focused ultrasound, light (near-infrared), or alternating magnetic fields permit spatiotemporal control over release. Thermo-sensitive liposomes or magnetoresponsive carriers can be used to ‘uncage’ TPs at a tumor site during a treatment session, providing on-demand delivery for potent but toxic agents [17,18]. Successful implementation of stimuli-responsive release requires balancing circulatory stability (to avoid premature release) with rapid responsiveness at the target. For TPs with narrow therapeutic windows, such triggers are particularly valuable to reduce systemic exposure while achieving high intratumoral concentrations. 4.4. Combination strategies and co-delivery Resistance to single-agent therapy is common in kinase-driven cancers. Nanocarriers easily accommodate co-loading of TPs with complementary therapeutics (chemotherapy, siRNA, immune modulators) to achieve synergistic effects and block escape pathways. Co-delivery can synchronize pharmacokinetics and ensure both agents reach the same cells at therapeutic ratios, something difficult to achieve with separate administrations [17,40]. Examples include TP PI3K inhibitors co-formulated with taxanes to overcome microtubule-targeted drug resistance, or TP + siRNA constructs that silence resistance mediators while inhibiting kinase signalling. Design challenges for co-delivery include differential solubility (hydrophilic vs hydrophobic cargo), release kinetics (matched vs staged release), and physicochemical compatibility. Layered architectures or core-shell formats can separate payloads and tune release profiles accordingly. World Journal of Advanced Research and Reviews, 2025, 27(02), 1858-1873 1866 4.5. Intracellular trafficking and endosomal escape For many TP targets (e.g., intracellular kinases), successful therapy requires delivery of active drug into the cytosol or nucleus. After receptor-mediated endocytosis, nanoparticles must traverse the endosomal pathway; endosomal entrapment leads to lysosomal degradation or slow release. Strategies to promote endosomal escape-proton sponge effect (cationic polymers), fusogenic peptides, and pH-responsive membrane-disrupting moieties are therefore integral to the design [35,36]. Careful selection of these features improves intracellular bioavailability of TPs and can markedly enhance potency while allowing lower dosing. 4.6. Imaging-guided targeting (theragnostic) Combining imaging probes with TP nano formulations enables non-invasive monitoring of biodistribution, target engagement, and therapeutic response. Co-encapsulated fluorophores, radiolabels, or MRI contrast agents provide PK/PD readouts that can inform dosing and patient selection, enhancing clinical translation [17,39]. Theragnostic TP systems are particularly attractive in early-phase trials to stratify responders and optimize schedules. 4.6.1. Practical takeaways for TP nano formulation design • Start with passive targeting (optimize size, PDI, and stealth) and layer active targeting only when a validated receptor is available. • Use stimuli-responsive release to confine exposure when TPs have narrow therapeutic windows. • For combination therapy, design matched release kinetics or staged delivery using modular architectures. • Incorporate endosomal escape features when intracellular delivery is required. • Consider theragnostic elements to de-risk translation via imaging-based patient selection and PK tracking [40]. 5. Case studies of thienopyrimidine-loaded nanoparticles While thienopyrimidines (TPs) have been well recognized as potent kinase inhibitors and antimicrobial scaffolds, their direct clinical application has been limited due to solubility, metabolic instability, and systemic toxicity. The incorporation of TPs into nanocarrier platforms has been explored in multiple preclinical studies to overcome these barriers. Below, selected case studies illustrate the design, performance, and therapeutic potential of nanothienopyrimidines. 5.1. Liposomal formulations of TP kinase inhibitors One of the earliest approaches involved liposomal encapsulation of TP-based kinase inhibitors to improve their pharmacokinetics. In a study by El-Sayed et al., liposomes loaded with a 2-thioxo-thieno[2,3-d] pyrimidine derivative demonstrated enhanced plasma stability and superior cytotoxicity against breast cancer cells compared to the free drug [41]. The liposomal system improved solubility and facilitated passive accumulation in tumor tissues via the EPR effect. Importantly, in vivo tumor growth inhibition was significantly higher in the liposomal group, underscoring the clinical potential of lipid-based carriers. 5.2. Polymeric nanoparticles for controlled delivery Polymeric nanoparticles (PNPs), particularly those fabricated from PLGA and PEG-PLGA copolymers, have been employed to deliver poorly soluble TP analogues. A TP-derived PI3K inhibitor encapsulated in PLGA nanoparticles showed sustained release over 72 h and significantly prolonged plasma half-life in rodent models [42]. When tested in xenograft tumors, PNPs achieved superior tumor growth suppression and reduced systemic toxicity compared to free drug administration. Targeted formulations using folate-modified PLGA further increased uptake in folate receptorpositive cancers [35]. 5.3. Solid lipid nanoparticles (SLNs) for oral delivery Given the poor oral bioavailability of many TP analogs, SLNs have been developed to improve gastrointestinal absorption. A TP-based antifungal compound formulated into SLNs exhibited more than a threefold increase in oral bioavailability in rat models relative to the free compound [43]. 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