Abstract: Cisplatin is a highly effective, first-line platinum-based chemotherapeutic agent widely used in the treatment of various solid tumors, including ovarian, breast, and colorectal cancers. Despite its potent anti-tumor activity, the clinical application of cisplatin is severely hindered by its lack of specificity, leading to dose-limiting systemic toxicities—most notably nephrotoxicity—and the development of cellular drug resistance. To address these challenges, recent research has heavily focused on targeted delivery systems. By utilizing nanotechnology (such as liposomes, polymeric nanoparticles, and metallic nanoclusters) and bioconjugation strategies (such as peptide and folate targeting), researchers have developed sophisticated platforms that enhance the accumulation of cisplatin in tumor tissues while sparing normal organs. Furthermore, advanced formulations like Pt(IV) prodrugs and glutathione-scavenging nanoparticles have been engineered to overcome resistance mechanisms and provide controlled, stimuli-responsive drug release. This review synthesizes recent advancements in targeted delivery systems for cisplatin, exploring their pharmacological activity, molecular mechanisms, structure-activity relationships, current limitations, and future clinical perspectives.
1. Introduction
Cisplatin (cis-diamminedichloroplatinum(II)) is a pioneering first-generation platinum-based anti-cancer drug that was discovered in the late 1960s and officially approved for clinical cancer treatment in 1978 [2]. It has demonstrated profound therapeutic efficacy against a variety of malignant solid tumors, including breast, ovarian, and colorectal cancers [1][2]. However, as a non-specific chemotherapeutic agent, cisplatin causes severe systemic toxicity alongside its tumor-killing effects. The most significant dose-limiting complication is nephrotoxicity, which often necessitates dose reduction or complete withdrawal of the therapy [1]. Other severe side effects include neurotoxicity, ototoxicity, and myelosuppression [2].
In addition to systemic toxicity, the long-term efficacy of cisplatin is frequently compromised by the development of drug resistance, which remains a major hurdle in clinical oncology [2][3]. To circumvent these limitations, extensive research has been directed toward the development of targeted delivery systems. By leveraging nanomaterial carriers, liposomal encapsulation, and bioconjugation with targeting moieties, these advanced delivery platforms aim to improve the bioavailability, enhance the anti-cancer efficiency, and significantly reduce the systemic toxicity of cisplatin [1][2].
2. Pharmacological Activity
The pharmacological activity of cisplatin is vastly improved when integrated into targeted delivery systems. Traditional cisplatin administration results in widespread distribution and rapid renal clearance, with 27–50% of the drug excreted by the kidneys within 48 hours, leading to acute kidney injury [1]. Nanocarriers—such as liposomes, polymeric nanoparticles (e.g., PLGA, chitosan), and metallic nanoparticles (e.g., gold nanoclusters, superparamagnetic iron oxide)—alter the pharmacokinetics of cisplatin by prolonging blood circulation time and facilitating passive accumulation in tumor tissues via the enhanced permeability and retention (EPR) effect [1][2].
For example, liposomal formulations like lipoplatin have successfully reached clinical trials, demonstrating the ability to maintain normal creatinine levels in patients while effectively inhibiting tumor growth [1]. In ovarian cancer models, targeted systems such as folate-drug conjugates and umbilical cord blood-derived macrophage exosomes have shown remarkable pharmacological activity by preferentially accumulating in cancer cells and reversing cisplatin resistance, resulting in significantly higher cytotoxicity compared to free cisplatin [3]. Furthermore, magnetic iron oxide nanoparticles loaded with cisplatin can be directed to specific tumor sites using an external magnetic field, enhancing local anti-cancer activity while sparing normal tissues like the spleen and kidneys [2].
3. Molecular Mechanism of Action
The classical molecular mechanism of cisplatin involves its cellular uptake followed by activation through hydrolysis. In the bloodstream, high chloride concentrations keep cisplatin stable. Upon entering the cell, the lower intracellular chloride concentration triggers the hydrolysis of cisplatin into highly reactive cationic species, such as [Pt(NH3)2Cl(OH2)]+ and [Pt(NH3)2(OH2)2]2+ [1]. These active derivatives bind to intracellular nucleophiles, primarily forming cross-links with purine residues on DNA. This DNA damage halts replication and transcription, ultimately inducing cellular apoptosis [1].
Targeted delivery systems modulate this mechanism to enhance efficacy and overcome resistance. One major mechanism of cisplatin resistance is the intracellular deactivation of the drug by endogenous thiols, particularly glutathione (GSH), which chelates platinum to form inactive adducts that are pumped out of the cell [2]. To counteract this, GSH-scavenging nanoparticles, such as poly(disulfide amide) polymers or sulforaphane-co-delivered systems, have been developed. These systems deplete intracellular GSH levels, thereby restoring the sensitivity of resistant cells to cisplatin and promoting severe DNA damage [1][2].
Additionally, many nanocarriers are engineered for stimuli-responsive release. For instance, pH-sensitive nanoparticles (like CaCO3 cores or specific polymeric micelles) remain stable at the physiological pH of 7.4 but rapidly collapse in the acidic extracellular environment of tumors (pH 5.5) or within acidic endosomes, ensuring that the active platinum species is released precisely where it is needed [1][2].
4. Structure-Activity Relationship (SAR)
The structure-activity relationship of platinum drugs has been extensively exploited to design targeted delivery systems. A prominent strategy is the conversion of square-planar Pt(II) complexes into octahedral Pt(IV) prodrugs. The Pt(IV) center is chemically inert in the bloodstream, which minimizes off-target toxicity. Upon entering the reductive environment of cancer cells, the Pt(IV) prodrug is reduced back to the active Pt(II) form, releasing its axial ligands [2].
The two additional axial positions on Pt(IV) prodrugs provide ideal attachment points for targeting moieties, significantly enhancing the SAR profile. For example, conjugating the cyclic tripeptide RGD allows the drug to specifically target integrin αvβ3, which is overexpressed on tumor cell membranes [2]. Similarly, the attachment of luteinizing hormone-releasing hormone (LHRH) peptides, biotin, or folic acid enables receptor-mediated endocytosis, selectively driving the platinum payload into breast, ovarian, or cervical cancer cells [1][2][3].
Polymeric encapsulation also relies on specific structural interactions. In cisplatin-polyacrylic acid (PAA) nanocapsules, the anionic chlorides of cisplatin are replaced by carboxylic residues from the polymer, which enhances drug loading capacity and prevents premature drug leakage [1]. Chitosan polymers interact with cisplatin through coordinate bonds between the polymer's carboxylic groups and the platinum atom, forming complexes that are stable at basic pH but break down in acidic tumor microenvironments [1].
5. Current Limitations
Despite the significant progress in targeted delivery, several limitations persist. The inherent toxicity of cisplatin remains a formidable challenge; even with nanocarriers, off-target accumulation can lead to nephrotoxicity, characterized by mitochondrial vacuolation, oxidative stress, and apoptosis in the proximal tubules of the kidney [1]. While nanoparticles reduce this burden, they are not entirely devoid of systemic effects.
Furthermore, the development of novel ultra-small platinum nanoclusters (Pt NCs) introduces new toxicological uncertainties. The precise structural characterization of these cluster molecules is difficult, and their dynamic in vivo metabolism, long-term fate, and potential cytotoxicity are not yet fully understood [2]. Delivery systems also face biological barriers; for instance, many nanoparticles are rapidly cleared by the reticuloendothelial system (RES) in the liver and spleen before reaching the tumor [1]. Finally, tumor heterogeneity and complex resistance mechanisms (such as enhanced DNA repair and altered membrane transport) mean that single-agent targeted delivery is sometimes insufficient to completely eradicate resistant tumors like ovarian cancer [3].
6. Future Perspectives
The future of cisplatin targeted delivery lies in the development of multifunctional, theranostic nanoplatforms. By integrating therapeutic platinum agents with diagnostic materials—such as gold nanoclusters for fluorescence imaging or superparamagnetic iron oxide for MRI—clinicians will be able to monitor drug distribution and tumor response in real time [2].
Synergistic combination therapies represent another highly promising frontier. Co-delivering cisplatin with other therapeutic modalities can overcome resistance and enhance efficacy. For example, nanoparticles co-loaded with cisplatin and catalase can decompose endogenous hydrogen peroxide into oxygen, thereby relieving tumor hypoxia and significantly boosting the efficacy of concurrent radiotherapy [4]. Additionally, combining platinum drugs with immune checkpoint inhibitors or utilizing multi-integrin targeting peptides will likely broaden the range of treatable tumors [2]. Moving forward, advanced analytical techniques, such as synchrotron radiation X-ray and mass spectrometry, will be crucial for understanding the in vivo biotransformation of platinum nanoclusters, ultimately guiding the rational design of safer and more effective clinical nanomedicines [2].
