Engineering a tumor-selective prodrug T-cell engager bispecific antibody for safer immunotherapy.

T-cell engaging (TCE) bispecific antibodies are potent drugs that trigger the immune system to eliminate cancer cells, but administration can be accompanied by toxic side effects that limit dosing. TCEs function by binding to cell surface receptors on T cells, frequently CD3, with one arm of the bispecific antibody while the other arm binds to cell surface antigens on cancer cells. On-target, off-tumor toxicity can arise when the target antigen is also present on healthy cells. The toxicity of TCEs may be ameliorated through the use of pro-drug forms of the TCE, which are not fully functional until recruited to the tumor microenvironment. This can be accomplished by masking the anti-CD3 arm of the TCE with an autoinhibitory motif that is released by tumor-enriched proteases. Here, we solve the crystal structure of the antigen-binding fragment of a novel anti-CD3 antibody, E10, in complex with its epitope from CD3 and use this information to engineer a masked form of the antibody that can activate by the tumor-enriched protease matrix metalloproteinase 2 (MMP-2). We demonstrate with binding experiments and in vitro T-cell activation and killing assays that our designed prodrug TCE is capable of tumor-selective T-cell activity that is dependent upon MMP-2. Furthermore, we demonstrate that a similar masking strategy can be used to create a pro-drug form of the frequently used anti-CD3 antibody SP34. This study showcases an approach to developing immune-modulating therapeutics that prioritizes safety and has the potential to advance cancer immunotherapy treatment strategies.

A novel selenium analog of HDACi-based twin drug induces apoptosis and cell cycle arrest via CDC25A to improve prostate cancer therapy.

Cancer therapy has moved from single agents to more mechanism-based targeted approaches. In recent years, the combination of HDAC inhibitors and other anticancer chemicals has produced exciting progress in cancer treatment. Herein, we developed a novel prodrug via the ligation of dichloroacetate to selenium-containing potent HDAC inhibitors. The effect and mechanism of this compound in the treatment of prostate cancer were also studied. Methods: The concerned prodrug SeSA-DCA was designed and synthesized under mild conditions. This compound's preclinical studies, including the pharmacokinetics, cell toxicity, and anti-tumor effect on prostate cancer cell lines, were thoroughly investigated, and its possible synergistic mechanism was also explored and discussed. Results: SeSA-DCA showed good stability in physiological conditions and could be rapidly decomposed into DCA and selenium analog of SAHA (SeSAHA) in the tumor microenvironment. CCK-8 experiments identified that SeSA-DCA could effectively inhibit the proliferation of a variety of tumor cell lines, especially in prostate cancer. In further studies, we found that SeSA-DCA could also inhibit the metastasis of prostate cancer cell lines and promote cell apoptosis. At the animal level, oral administration of SeSA-DCA led to significant tumor regression without obvious toxicity. Moreover, as a bimolecular coupling compound, SeSA-DCA exhibited vastly superior efficacy than the mixture with equimolar SeSAHA and DCA both in vitro and in vivo. Our findings provide an important theoretical basis for clinical prostate cancer treatment. Conclusions: Our in vivo and in vitro results showed that SeSA-DCA is a highly effective anti-tumor compound for PCa. It can effectively induce cell cycle arrest and growth suppression and inhibit the migration and metastasis of PCa cell lines compared with monotherapy. SeSA-DCA's ability to decrease the growth of xenografts is a little better than that of docetaxel without any apparent signs of toxicity. Our findings provide an important theoretical basis for clinical prostate cancer treatment.

High-temperature PTT/CDT coordination nanoplatform realizing exacerbated hypoxia for enhancing hypoxia-activated chemotherapy to overcome tumor drug resistance.

BACKGROUND: Hypoxia-activated prodrugs present new opportunities for safe and effective tumor drug resistance therapy due to their high selectivity for hypoxic cells. However, the uneven distribution of oxygen in solid tumor and insufficient hypoxia in the tumor microenvironment greatly limit its therapeutic efficacy. RESULTS: In this paper, a novel AQ4N-Mn(II)@PDA coordination nanoplatform was designed and functionalized with GMBP1 to target drug-resistant tumor cells. Its excellent photothermal conversion efficiency could achieve local high-temperature photothermal therapy in tumors, which could not only effectively exacerbate tumor hypoxia and thus improve the efficacy of hypoxia-activated chemotherapy of AQ4N but also significantly accelerate Mn2+-mediated Fenton-like activity to enhance chemodynamic therapy. Moreover, real-time monitoring of blood oxygen saturation through photoacoustic imaging could reflect the hypoxic status of tumors during treatment. Furthermore, synergistic treatment effectively inhibited tumor growth and improved the survival rate of mice bearing orthotopic drug-resistant tumors. CONCLUSIONS: This study not only provided a new idea for PTT combined with hypoxia-activated chemotherapy and CDT for drug-resistant tumors but also explored a vital theory for real-time monitoring of hypoxia during treatment.

Supramolecular assembly of isomeric SN-38 prodrugs regulated by conjugation sites.

Supramolecular polymers (SPs) are an emerging class of drug transporters employed to improve drug therapy. Through the rational design of self-assembling monomers, one can optimize the properties of the resulting supramolecular nanostructures, such as size, shape, surface chemistry, release, and, therefore, biological fates. This study highlights the design of isomeric SN38 prodrugs through the conjugation of hydrophilic oligo(ethylene glycol) (OEG) with hydroxyls at positions 10 and 20 on hydrophobic SN-38. Self-assembling prodrug (SAPD) isomers 10-OEG-SN38 and 20-OEG-SN38 can self-assemble into giant nanotubes and filamentous assemblies, respectively, via aromatic associations that dominate self-assembly. Our study reveales the influence of modification sites on the assembly behavior and ability of the SN38 SAPDs, as well as drug release and subsequent in vitro and in vivo antitumor effects. The SAPD modified at position 20 exhibits stronger π-π interactions among SN38 units, leading to more compact packing and enhanced assembly capability, whereas OEG at position 10 poses steric hindrance for aromatic associations. Importantly, owing to its higher chemical and supramolecular stability, 20-OEG-SN38 outperforms 10-OEG-SN38 and irinotecan, a clinically used prodrug of SN38, in a CT26 tumor model, demonstrating enhanced tumor growth inhibition and prolonged animal survival. This study presents a new strategy of using interactions among drug molecules as dominating features to create supramolecular assemblies. It also brings some insights into creating effective supramolecular drug assemblies via the engineering of self-assembling building blocks, which could contribute to the optimization of design principles for supramolecular drug delivery systems.

Sulfoxide-containing polymers conjugated prodrug micelles with enhanced anticancer activity and reduced intestinal toxicity.

Poly(ethylene glycol) (PEG) is widely utilized as a hydrophilic coating to extend the circulation time and improve the tumor accumulation of polymeric micelles. Nonetheless, PEGylated micelles often activate complement proteins, leading to accelerated blood clearance and negatively impacting drug efficacy and safety. Here, we have crafted amphiphilic block copolymers that merge hydrophilic sulfoxide-containing polymers (psulfoxides) with the hydrophobic drug 7-ethyl-10-hydroxylcamptothecin (SN38) into drug-conjugate micelles. Our findings show that the specific variant, PMSEA-PSN38 micelles, remarkably reduce protein fouling, prolong blood circulation, and improve intratumoral accumulation, culminating in significantly increased anti-cancer efficacy compared with PEG-PSN38 counterpart. Additionally, PMSEA-PSN38 micelles effectively inhibit complement activation, mitigate leukocyte uptake, and attenuate hyperactivation of inflammatory cells, diminishing their ability to stimulate tumor metastasis and cause inflammation. As a result, PMSEA-PSN38 micelles show exceptional promise in the realm of anti-metastasis and significantly abate SN38-induced intestinal toxicity. This study underscores the promising role of psulfoxides as viable PEG substitutes in the design of polymeric micelles for efficacious anti-cancer drug delivery.

Characterization and Hydrolysis Studies of a Prodrug Obtained as Ester Conjugate of Geraniol and Ferulic Acid by Enzymatic Way.

Ferulic acid (Fer) and geraniol (Ger) are natural compounds whose antioxidant and anti-inflammatory activity confer beneficial properties, such as antibacterial, anticancer, and neuroprotective effects. However, the short half-lives of these compounds impair their therapeutic activities after conventional administration. We propose, therefore, a new prodrug (Fer-Ger) obtained by a bio-catalyzed ester conjugation of Fer and Ger to enhance the loading of solid lipid microparticles (SLMs) designed as Fer-Ger delivery and targeting systems. SLMs were obtained by hot emulsion techniques without organic solvents. HPLC-UV analysis evidenced that Fer-Ger is hydrolyzed in human or rat whole blood and rat liver homogenates, with half-lives of 193.64 ± 20.93, 20.15 ± 0.75, and 3.94 ± 0.33 min, respectively, but not in rat brain homogenates. Studies on neuronal-differentiated mouse neuroblastoma N2a cells incubated with the reactive oxygen species (ROS) inductor H2O2 evidenced the Fer-Ger ability to prevent oxidative injury, despite the fact that it appears ROS-promoting. The amounts of Fer-Ger encapsulated in tristearin SLMs, obtained in the absence or presence of glucose, were 1.5 ± 0.1%, allowing the control of the prodrug release (glucose absence) or to sensibly enhance its water dissolution rate (glucose presence). These new "green" carriers can potentially prolong the beneficial effects of Fer and Ger or induce neuroprotection as nasal formulations.

A chiral trimethyl lock based on the vicinal disubstituent effect: prolonged release of camptothecin into cancer cells.

Synthesis and in vitro testing of a prodrug designed for the controlled delivery of the anticancer drug camptothecin within pancreatic cancer cells are reported. Our study reveals a non-conventional pharmacokinetic release characterized by an exponential pattern before reaching the half-life (t1/2) and a linear pattern thereafter. The release mechanism was triggered either by hydrolytic enzymes and/or by the acid microenvironment of cancer cells.

PLX038A, a long-acting SN-38, penetrates the blood-tumor-brain-barrier, accumulates and releases SN-38 in brain tumors to increase survival of tumor bearing mice.

Central nervous system tumors have resisted effective chemotherapy because most therapeutics do not penetrate the blood-tumor-brain-barrier. Nanomedicines between ~ 10 and 100 nm accumulate in many solid tumors by the enhanced permeability and retention effect, but it is controversial whether the effect can be exploited for treatment of brain tumors. PLX038A is a long-acting prodrug of the topoisomerase 1 inhibitor SN-38. It is composed of a 15 nm 4-arm 40 kDa PEG tethered to four SN-38 moieties by linkers that slowly cleave to release the SN-38. The prodrug was remarkably effective at suppressing growth of intracranial breast cancer and glioblastoma (GBM), significantly increasing the life span of mice harboring them. We addressed the important issue of whether the prodrug releases SN-38 systemically and then penetrates the brain to exert anti-tumor effects, or whether it directly penetrates the blood-tumor-brain-barrier and releases the SN-38 cargo within the tumor. We argue that the amount of SN-38 formed systemically is insufficient to inhibit the tumors, and show by PET imaging that a close surrogate of the 40 kDa PEG carrier in PLX038A accumulates and is retained in the GBM. We conclude that the prodrug penetrates the blood-tumor-brain-barrier, accumulates in the tumor microenvironment and releases its SN-38 cargo from within. Based on our results, we pose the provocative question as to whether the 40 kDa nanomolecule PEG carrier might serve as a "Trojan horse" to carry other drugs past the blood-tumor-brain-barrier and release them into brain tumors.

Sonodynamic and sonomechanical effect on cellular stemness and extracellular physicochemical environment to potentiate chemotherapy.

BACKGROUND: Hypoxia-activated prodrug (HAP) is a promising candidate for highly tumor-specific chemotherapy. However, the oxygenation heterogeneity and dense extracellular matrix (ECM) of tumor, as well as the potential resistance to chemotherapy, have severely impeded the resulting overall efficacy of HAP. RESULTS: A HAP potentiating strategy is proposed based on ultrasound responsive nanodroplets (PTP@PLGA), which is composed of protoporphyrin (PpIX), perfluoropropane (PFP) and a typical HAP, tirapazamine (TPZ). The intense vaporization of PFP upon ultrasound irradiation can magnify the sonomechanical effect, which loosens the ECM to promote the penetration of TPZ into the deep hypoxic region. Meanwhile, the PpIX enabled sonodynamic effect can further reduce the oxygen level, thus activating the TPZ in the relatively normoxic region as well. Surprisingly, abovementioned ultrasound effect also results in the downregulation of the stemness of cancer cells, which is highly associated with drug-refractoriness. CONCLUSIONS: This work manifests an ideal example of ultrasound-based nanotechnology for potentiating HAP and also reveals the potential acoustic effect of intervening cancer stem-like cells.

Mucoadhesive Mesalamine Prodrug Nanoassemblies to Target Intestinal Macrophages for the Treatment of Inflammatory Bowel Disease.

While mesalamine, a 5-aminosalicylic acid (5-ASA), is pivotal in the management of inflammatory bowel disease (IBD) through both step-up and top-down approaches in clinical settings, its widespread utilization is limited by low bioavailability at the desired site of action due to rapid and extensive absorption in the upper gastrointestinal (GI) tract. Addressing mesalamine's pharmacokinetic challenges, here, we introduce nanoassemblies composed exclusively of a mesalamine prodrug that pairs 5-ASA with a mucoadhesive and cathepsin B-cleavable peptide. In an IBD model, orally administered nanoassemblies demonstrate enhanced accumulation and sustained retention in the GI tract due to their mucoadhesive properties and the epithelial enhanced permeability and retention (eEPR) effect. This retention enables the efficient uptake by intestinal pro-inflammatory macrophages expressing high cathepsin B, triggering a burst release of the 5-ASA. This cascade fosters the polarization toward an M2 macrophage phenotype, diminishes inflammatory responses, and simultaneously facilitates the delivery of active agents to adjacent epithelial cells. Therefore, the nanoassemblies show outstanding therapeutic efficacy in inhibiting local inflammation and contribute to suppressing systemic inflammation by restoring damaged intestinal barriers. Collectively, this study highlights the promising role of the prodrug nanoassemblies in enhancing targeted drug delivery, potentially broadening the use of mesalamine in managing IBD.

Anticancer nano-prodrugs with drug release triggered by intracellular dissolution and hydrogen peroxide response.

We developed prodrug nanoparticles that release drugs through intracellular dissolution and a cancer-specific hydrogen peroxide response. To reveal the unclear mechanism regarding drug release from nanoparticles by reacting with hydrogen peroxide in cancer cells, this study demonstrates the in vitro evaluation of drug release kinetics under conditions simulated in cancer cells.

Structural Evaluation of a Nitroreductase Engineered for Improved Activation of the 5-Nitroimidazole PET Probe SN33623.

Bacterial nitroreductase enzymes capable of activating imaging probes and prodrugs are valuable tools for gene-directed enzyme prodrug therapies and targeted cell ablation models. We recently engineered a nitroreductase (E. coli NfsB F70A/F108Y) for the substantially enhanced reduction of the 5-nitroimidazole PET-capable probe, SN33623, which permits the theranostic imaging of vectors labeled with oxygen-insensitive bacterial nitroreductases. This mutant enzyme also shows improved activation of the DNA-alkylation prodrugs CB1954 and metronidazole. To elucidate the mechanism behind these enhancements, we resolved the crystal structure of the mutant enzyme to 1.98 Å and compared it to the wild-type enzyme. Structural analysis revealed an expanded substrate access channel and new hydrogen bonding interactions. Additionally, computational modeling of SN33623, CB1954, and metronidazole binding in the active sites of both the mutant and wild-type enzymes revealed key differences in substrate orientations and interactions, with improvements in activity being mirrored by reduced distances between the N5-H of isoalloxazine and the substrate nitro group oxygen in the mutant models. These findings deepen our understanding of nitroreductase substrate specificity and catalytic mechanisms and have potential implications for developing more effective theranostic imaging strategies in cancer treatment.

Anticancer Prodrug Capable of Mitochondria-Targeting, Light-Triggered Release, and Fluorescence Monitoring.

Mitigating the adverse effects of anticancer agents requires innovative prodrug engineering. In this study, we showcase the potential of our o-quinone methide-based trigger-release-conjugation platform as a versatile tool for constructing advanced prodrug systems. Using this platform, we achieved the light-triggered release of an anticancer drug mechlorethamine, targeting mitochondrial DNA. The entire process was adeptly tracked through the emission of fluorescence signals, revealing notable effects across various cancer cell lines compared to a normal cell line. Exploring alternative cancer-associated triggers, including enzymes, and incorporating cancer/tumor-specific targeting elements could lead to effective prodrugs with reduced cytotoxicity.

Iterative Design Reveals Molecular Domain Relationships in Supramolecular Peptide-Drug Conjugates.

Supramolecular peptide-drug conjugates (sPDCs) are prepared by covalent attachment of a drug moiety to a peptide motif programmed for one-dimensional self-assembly, with subsequent physical entanglement of these fibrillar structures enabling formation of nanofibrous hydrogels. This class of prodrug materials presents an attractive platform for mass-efficient and site-specific delivery of therapeutic agents using a discrete, single-component molecular design. However, a continued challenge in sPDC development is elucidating relationships between supramolecular interactions in their drug and peptide domains and the resultant impacts of these domains on assembly outcomes and material properties. Inclusion of a saturated alkyl segment alongside the prodrug in the hydrophobic domain of sPDCs could relieve some of the necessity for ordered, prodrug-produg interactions. Accordingly, nine sPDCs are prepared here to iterate the design variables of amino acid sequence and hydrophobic prodrug-alkyl block design. All molecules spontaneously formed hydrogels under physiological conditions, indicating a less hindered thermodynamic path to self-assembly relative to previous prodrug-only designs. However, material studies on the supramolecular arrangement, formation, and mechanical properties of the resultant sPDC hydrogels as well as their drug release profiles showed complex relationships between the hydrophobic and peptide domains in the formation and function of the resulting assemblies. Together, these results indicate that sPDC material properties are intrinsically linked to holistic molecular design with coupled contributions from their prodrug and peptide domains in directing properties of the emergent materials.

Enhancing anticancer treatment: Development of cRGD-Conjugated F-OH-Evo prodrugs for targeted delivery.

Small molecule drugs sourced from natural products are pivotal for novel therapeutic discoveries. However, their clinical deployment is often impeded by non-specific activity and severe adverse effects. This study focused on 3-fluoro-10-hydroxy-Evodiamine (F-OH-Evo), a potent derivative of Evodiamine, whose development is curtailed due to suboptimal tumor selectivity and heightened cytotoxicity. By harnessing the remarkable stability, specificity, and αvß3 integrin affinity of c(RGDFK), a novel prodrug by conjugating F-OH-Evo with cRGD was synthesized. This innovative prodrug substantially enhanced the tumor-specific targeting of F-OH-Evo and improved the anti-tumor activities. Among them, compound 3c demonstrated the best selective inhibitory activity toward U87 cancer cells in vitro. It selectively enterd U87 cells by binding to αvß3 integrin, releasing the parent molecule under the dual response of ROS and GSH to exert inhibitory activity on topo I. The results highlight the potential of cRGD-conjugated prodrugs in targeted cancer therapy. This approach signifies a significant advancement in developing safer and more effective chemotherapy drugs, emphasizing the role of prodrug strategies in overcoming the limitations of traditional cancer treatments.

Metal-based carbon monoxide releasing molecules with promising cytotoxic properties.

Carbon monoxide, the "silent killer" gas, is increasingly recognised as an important signalling molecule in human physiology, which has beneficial biological properties. A particular way of achieving controlled CO administration is based on the use of biocompatible molecules that only release CO when triggered by internal or external factors. These approaches include the development of pharmacologically effective prodrugs known as CO releasing molecules (CORMs), which can supply biological systems with CO in well-regulated doses. An overview of transition metal-based CORMs with cytotoxic properties is here reported. The mechanisms at the basis of the biological activities of these molecules and their potential therapeutical applications with respect to their stability and CO releasing properties have been discussed. The activation of metal-based CORMs is determined by the type of metal and by the nature and features of the auxiliary ligands, which affect the metal core electronic density and therefore the prodrug resistance towards oxidation and CO release ability. A major role in regulating the cytotoxic properties of these CORMs is played by CO and/or CO-depleted species. However, several mysteries concerning the cytotoxicity of CORMs remain as intriguing questions for scientists.

Differential Bioactivation Profiles of Different GS-441524 Prodrugs in Cell and Mouse Models: ProTide Prodrugs with High Cell Permeability and Susceptibility to Cathepsin A Are More Efficient in Delivering Antiviral Active Metabolites to the Lung.

We assessed factors that determine the tissue-specific bioactivation of ProTide prodrugs by comparing the disposition and activation of remdesivir (RDV), its methylpropyl and isopropyl ester analogues (MeRDV and IsoRDV, respectively), the oral prodrug GS-621763, and the parent nucleotide GS-441524 (Nuc). RDV and MeRDV yielded more active metabolite remdesivir-triphosphate (RDV-TP) than IsoRDV, GS-621763, and Nuc in human lung cell models due to superior cell permeability and higher susceptivity to cathepsin A. Intravenous administration to mice showed that RDV and MeRDV delivered significantly more RDV-TP to the lung than other compounds. Nevertheless, all four ester prodrugs exhibited very low oral bioavailability (<2%), with Nuc being the predominant metabolite in blood. In conclusion, ProTides prodrugs, such as RDV and MeRDV, are more efficient in delivering active metabolites to the lung than Nuc, driven by high cell permeability and susceptivity to cathepsin A. Optimizing ProTides' ester structures is an effective strategy for enhancing prodrug activation in the lung.

Microbial ß-Glucuronidase Hydrogel Beads Activate Chemotherapeutic Prodrug.

Bacteria-assisted chemotherapeutics have been highlighted as an alternative or supplementary approach to treating cancer. However, dynamic cancer-microbe studies at the in vitro level have remained a challenge to show the impact and effectiveness of microbial therapeutics due to the lack of relevant coculture models. Here, we demonstrate a hydrogel-based compartmentalized system for prodrug activation of a natural ingredient of licorice root, glycyrrhizin, by microbial ß-glucuronidase (GUS). Hydrogel containment with Lactococcus lactis provides a favorable niche to encode GUS enzymes with excellent permeability and can serve as an independent ecosystem in the transformation of pro-apoptotic materials. Based on the confinement system of GUS expressing microbes, we quantitatively evaluated chemotherapeutic effects enhanced by microbial GUS enzyme in two dynamic coculture models in vitro (i.e., 2D monolayered cancer cells and 3D tumor spheroids). Our findings support the processes of prodrug conversion mediated by bacterial GUS enzyme which can enhance the therapeutic efficacy of a chemotherapy drug under dynamic coculture conditions. We expect our in vitro coculture platforms can be used for the evaluation of pharmacological properties and biological activity of xenobiotics as well as the potential impact of microbes on cancer therapeutics.

Multiaction Pt(IV) Prodrugs Releasing Cisplatin and Dasatinib Are Potent Anticancer and Anti-Invasive Agents Displaying Synergism between the Two Drugs.

Herein, we describe the general design, synthesis, characterization, and biological activity of new multitargeting Pt(IV) prodrugs that combine antitumor cisplatin and dasatinib, a potent inhibitor of Src kinase. These prodrugs exhibit impressive antiproliferative and anti-invasive activities in tumor cell lines in both two-dimensional (2D) monolayers of cell cultures and three-dimensional (3D) spheroids. We show that the cisplatin moiety and dasatinib in the investigated Pt(IV) complexes are both involved in the mechanism of action in MCF7 breast cancer cells and act synergistically. Thus, combining dasatinib and cisplatin into one molecule, compared to using individual components in a mix, may bring several advantages, such as significantly higher activity in cancer cell lines and higher selectivity for tumor cells. Most importantly, Pt(IV)-dasatinib complexes hold significant promise for potential anticancer therapies by targeting epithelial-mesenchymal transition, thus preventing the spread and metastasis of tumors, a value unachievable by a simple combination of both individual components.

Light-Responsive Pt(IV) Prodrugs with Controlled Photoactivation and Low Dark Toxicity.

Light-induced release of cisplatin from Pt(IV) prodrugs represents a promising approach for precise control over the antiproliferative activity of Pt-based chemotherapeutic drugs. This method has the potential to overcome crucial drawbacks of conventional cisplatin therapy, such as high general toxicity toward healthy organs and tissues. Herein, we report two Pt(IV) prodrugs with BODIPY-based photoactive ligands Pt-1 and Pt-2, which were designed using carbamate and triazole linkers, respectively. Both prodrugs demonstrated the ability to release cisplatin under blue light irradiation without the requirement of an external reducing agent. Dicarboxylated Pt-2 prodrug turned out to be more stable in the dark and more sensitive to light than its monocarbamate Pt-1 counterpart; these observations were explained using DFT calculations. The investigation of the photoreduction mechanism of Pt-1 and Pt-2 prodrugs using DFT modeling and ΔG0 PET estimation suggests that the photoinduced electron transfer from the singlet excited state of the BODIPY axial ligand to the Pt(IV) center is the key step in the light-induced release of cisplatin from the complexes. Cytotoxicity studies demonstrated that both prodrugs were nontoxic in the dark and toxic to MCF-7 cells under low-dose irradiation with blue light, and the observed effect was solely due to the cisplatin release from the Pt(IV) prodrugs. Our research presents an elegant synthetic approach to light-activated Pt(IV) prodrugs and presents findings that may contribute to the future rational design of photoactivatable Pt(IV) prodrugs.