Prodrug Of SN-38 Research Articles

Multimodal enhancement of ferroptosis for synergistic cascade colorectal cancer therapy

Emerging research positions ferroptosis as a formidable anti-tumor modality for colorectal cancer (CRC). However, the current pathways to potentiate ferroptosis through a singular or dual approach have fallen short in maximizing treatment efficacy. Herein, a multimodal enhancement strategy of ferroptosis is achieved for synergistic cascade colorectal cancer therapy, via clinical-related drug repurposing and prodrug self-assembly of SN38 and sulfasalazine (SAS). In this process, the SN38 or SAS prodrug is synthesized by conjugating ferrocene via disulfide bonds to SN38 or SAS, then the two prodrugs self-assemble into a hybrid nanomedicine (FSS). FSS exhibited pronounced stability under physiological conditions, while demonstrating rapid disassembly via glutathione-responsive break of disulfide bonds in tumor microenvironments. Then, a multimodal enhancement strategy of cancer ferroptosis is achieved via the SAS-induced regulation of amino acid metabolism, SN38-resulted regulation of glutathione synthesis, accumulation of ferroptosis-related lipid signaling, and ferrocene-directed iron overload in tumors. The potent ferroptosis-based CRC anticancer effects of FSS were systematically explored and confirmed by comprehensive in vitro and in vivo analyses, including cellular experiments, subcutaneous and orthotopic tumor-bearing mouse models, and RNA-sequencing transcriptomic studies. This study lays the groundwork for the clinical translation of multimodal ferroptosis inducers, offering an effective and safe approach to cancer treatment.

Carrier-free nano-prodrugs for minimally invasive cancer therapy.

An anticancer nanodrug with few side effects that does not require the use of a nanocarrier, polyethylene glycol, or other additives has been developed. We have fabricated nano-prodrugs (NPDs) composed only of homodimeric prodrugs of the anticancer agent SN-38, which contains a disulfide bond. The prodrugs are stable against hydrolysis but selectively release SN-38 when the disulfide bond is cleaved by glutathione, which is present in high concentrations in cancer cells. The best-performing NPDs showed good dispersion stability in nanoparticle form, and animal experiments revealed that they possess much higher antitumor activity than irinotecan, a clinically applied prodrug of SN-38. This performance was achieved by improving tumor accumulation due to the size effect and targeted drug release mechanism. The present study provides an insight into the development of non-invasive NPDs with high pharmacological activity, and also offers new possibilities for designing prodrug molecules that can release drugs in response to various kinds of triggers.

In vitro evaluation of novel SN-38 prodrug activated by α-rhamnosidase of exogenous enzyme.

This study introduces the α-rhamnose (Rham)-conjugated prodrug of SN-38 (Rham-SN-38) as a promising alternative to irinotecan. α-rhamnosidase, responsible for SN-38 release from Rham-SN-38, does not express in human cells, minimizing individual variability and side effects. The injection of the α-rhamnosidase into the tumor tissues makes it possible, for the first time, to activate the Rham-SN-38. Furthermore, α-rhamnosidase demonstrates significantly higher activity than carboxylesterase, the specific enzyme activating irinotecan. SN-38 release mediated by α-rhamnosidase completes within 2h, with a kcat/Km value approximately 5.0 × 104-fold higher than that of irinotecan. The 50% inhibition concentration (IC50) of Rham-SN-38 against three types of cancer cells and one normal cell exceeds 4.5 × 103nM. The addition of α-rhamnosidase significantly increases cytotoxicity, with IC50 comparable to free SN-38. The QIC50, an index reflecting the difference in cytotoxicity with and without α-rhamnosidase, exceeds approximately 1.0 × 102-fold. Rham-SN-38, synthesized in this study, demonstrates significant potential as a prodrug for cancer therapy.

Supramolecular prodrug of SN38 based on endogenous albumin and SN38 prodrug modified with semaglutide side chain to improve the tumor distribution

To improve the biodistribution of the drug in the tumor, a supramolecular prodrug of SN38 was fabricated in situ between endogenous albumin and SN38 prodrug modified with semaglutide side chain. Firstly, SN38 was conjugated with semaglutide side chain and octadecanedioic acid via glycine linkers to obtain SI-Gly-SN38 and OA-Gly-SN38 prodrugs, respectively. Both SI-Gly-SN38 and OA-Gly-SN38 exhibited excellent stability in PBS for over 24 h. Due to the strong binding affinity of the semaglutide side chain with albumin, the plasma half-life of SI-Gly-SN38 was 2.7 times higher than that of OA-Gly-SN38. Furthermore, with addition of HSA, the fluorescence intensity of SI-Gly-SN38 was 4 times higher than that of OA-Gly-SN38, confirming its strong binding capability with HSA. MTT assay showed that the cytotoxicity of SI-Gly-SN38 and OA-Gly-SN38 was higher than that of Irinotecan. Even incubated with HSA, the SI-Gly-SN38 and OA-Gly-SN38 still maintained high cytotoxicity, indicating minimal influence of HSA on their cytotoxicity. In vivo pharmacokinetic studies demonstrated that the circulation half-life of SI-Gly-SN38 was twice that of OA-Gly-SN38. SI-Gly-SN38 exhibited significantly reduced accumulation in the lungs, being only 0.23 times that of OA-Gly-SN38. The release of free SN38 in the lungs from SI-Gly-SN38 was only 0.4 times that from OA-Gly-SN38 and Irinotecan. The SI-Gly-SN38 showed the highest accumulation in tumors. The tumor inhibition rate of SI-Gly-SN38 was 6.42% higher than that of OA-Gly-SN38, and 8.67% higher than that of Irinotecan, respectively. These results indicate that the supramolecular prodrug delivery system can be constructed between SI-Gly-SN38 and endogenous albumin, which improves drug biodistribution in vivo, enhances tumor accumulation, and plays a crucial role in tumor growth inhibition.

Design, synthesis, and biological evaluation of cathepsin B cleavage albumin-binding SN38 prodrug in breast cancer

Here, we introduce a novel and effective approach utilizing a cathepsin B cleavage albumin-binding SN38 prodrug specifically designed for the treatment of metastatic breast cancer. Termed Mal-va-mac-SN38, our prodrug exhibits a unique ability to rapidly and covalently bind with endogenous albumin, resulting in the formation of HSA-va-mac-SN38. This prodrug demonstrates exceptional stability in human plasma. Importantly, HSA-va-mac-SN38 showcases an impressive enhancement in cellular uptake by 4T1 breast cancer cells, primarily facilitated through caveolin-mediated endocytosis. Intriguingly, the release of the active SN38, is triggered by the enzymatic activity of cathepsin B within the lysosomal environment. In vivo studies employing a lung metastasis 4T1 breast cancer model underscore the potency of HSA-va-mac-SN38. Histological immunohistochemical analyses further illuminate the multifaceted impact of our prodrug, showcasing elevated levels of apoptosis, downregulated expression of matrix metalloproteinases, and inhibition of angiogenesis, all critical factors contributing to the anti-metastatic effect observed. Biodistribution studies elucidate the capacity of Mal-va-mac-SN38 to augment tumor accumulation through covalent binding to serum albumin, presenting a potential avenue for targeted therapeutic interventions. Collectively, our findings propose a promising therapeutic avenue for metastatic breast cancer, through the utilization of a cathepsin B-cleavable albumin-binding prodrug.

Enhancing SN38 prodrug delivery using a self-immolative linker and endogenous albumin transport

Enhancing the delivery and release efficiency of hydroxyl agents, constrained by high pKa values and issues of release rate or unstable linkage, is a critical challenge. To address this, a self-immolative linker, composed of a modifiable p-hydroxybenzyl ether and a fast cyclization adapter (N-(ortho-hydroxyphenyl)-N-methylcarbamate) was strategically designed, for the synthesis of prodrugs. The innovative linker not only provides a side chain modification but also facilitates the rapid release of the active payloads, thereby enabling precise drug delivery. Particularly, five prodrug model compounds (J1, J2, J3, J5 and J6) were synthesized to evaluate the release rates by using β-glucuronic acid as trigger and five hydroxyl compounds as model payloads. Significantly, all prodrug model compounds could efficiently release the hydroxyl payloads under the action of β-glucuronidase, validating the robustness of the linker. And then, to assess the drug delivery and release efficiency using endogenous albumin as a transport vehicle, J1148, a SN38 prodrug modified with maleimide side chain was synthesized. Results demonstrated that J1148 covalently bound to plasma albumin through in situ Michael addition, effectively targeting the tumor microenvironment. Activated by β-glucuronidase, J1148 underwent a classical 1, 6-elimination, followed by rapid cyclization of the adapter, thereby releasing SN38. Impressively, J1148 showed excellent therapeutic efficacy against human colonic cancer xenograft model, leading to a significant reduction or even disappearance of tumors (3/6 of mice cured). These findings underscore the potential of the designed linker in the delivery system of hydroxyl agents, positioning it at the forefront of advancements in drug delivery technology.

Could a Long-Acting Prodrug of SN-38 be Efficacious in Sacituzumab Govitecan-Resistant Tumors?

We previously proposed that sacituzumab govitecan (SG, Trodelvy®) likely acts as a simple prodrug of systemic SN-38 as well as an antibody drug conjugate (ADC). In the present commentary, we assess whether a long-acting SN-38 prodrug, such as PLX038, might be efficacious in SG-resistant patients. We first describe possible mechanisms of action of SG, with new insights on pharmacokinetics and TROP2 receptor occupancy. We argue that SG is not an optimal conventional ADC and that the amount of systemic SN-38 spontaneously hydrolyzed from the ADC is so high it must have activity. Then, we describe the concept of time-over-target as related to the pharmacology of SG and PLX038 as SN-38 prodrugs. To be clear, we are not in any way suggesting that PLX038 or any SN-38 prodrug is superior to SG as an anticancer agent. Clearly, SG has the benefit over antigen-independent SN-38 prodrugs in that it targets cells with the TROP2 receptor. However, we surmise that PLX038 should be a more efficacious and less toxic prodrug of systemic SN-38 than SG. Finally, we suggest possible mechanisms of SG resistance and how PLX038 might perform in the context of each. Taken together, we argue that-contrary to many opinions-SG does not exclusively act as a conventional ADC, and propose that PLX038 may be efficacious in some settings of SG-resistance.

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.

Abstract A140: A physiologically based pharmacokinetic modeling approach for predicting the exposure of irinotecan and its active metabolite (SN-38) in cancer patients

Abstract Introduction: Irinotecan is an inhibitor of the topoisomerase I enzyme that is essential in DNA transcription, replication, and repair. It is considered a “backbone” regime in colorectal cancer in adults and in pediatric gliomas to which other antineoplastic agents are added to improve the outcome. It is used as well in the treatment of many other types of adult and pediatric cancers. Irinotecan acts as a prodrug of SN-38 which has approximately 100-1000-fold greater cytotoxic activity. The metabolic and pharmacokinetic behavior of irinotecan is very complex and currently not completely elucidated. Clinical data have shown high variability in treated patients in the efficacy, toxicity, and pharmacokinetic profile of the drug. To increase safety and efficacy, a physiologically based pharmacokinetic modeling (PBPK) approach was used to predict the optimal dose for treatment initiation. Methods: Clinical data were used in combination with measured physicochemical and blood-binding data to inform the model. Hence a middle-out approach was used to build the parent model for a population of adult cancer patients. While the default Sim-Cancer population available within the Simcyp Simulator (v21) was used, the unbound fraction in plasma for the healthy population was incorporated into the PBPK model. By using the reverse translational tool and a retrograde approach, the irinotecan metabolism was described by incorporating CYP3A (Km 14.4±1.6 μM, Vmax 14.7± 0.6 pmol/min/mg protein) and an additional clearance. This additional clearance was then explained by scaled esterases (CES1 and CES2) enzyme kinetic from in vitro data. Besides the clinical study that was used to build the model, other independent intravenously administered irinotecan studies were used for verification. Results: The model predicted the plasma concentration of the parent drug and its metabolite (SN-38) in good agreement with observed data from the clinical study that was used to build the model, as well as from several clinical studies that were not used to build the initial model, covering a dose range of 50-750 mg/m2. Conclusion: We developed a PBPK model that accurately predicts the pharmacokinetic behavior of irinotecan and its metabolite (SN-38) in an adult cancer population. Future directions involve the adaption of the model to the pediatric cancer population to predict the optimal dose for initiation of first-in-human Phase I studies and to identify potential drug interactions and unanticipated toxicities when this “backbone” regimen is combined with other investigated anticancer agents. This will then lead to an increase in individualized treatment. Citation Format: Kristina Zoran Denic, Sibylle Neuhoff, Joel Reid, Rachel Kudget. A physiologically based pharmacokinetic modeling approach for predicting the exposure of irinotecan and its active metabolite (SN-38) in cancer patients [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A140.

Inhibitory effects of NSAID-conjugated SN-38 on the viability of A549 Non-small cell lung cancer cells

The goal of this paper was to look into the anti-tumor mechanism of Non-Steroidal Anti-Inflammatory Drug (NSAID)-conjugated SN-38 Prodrug in A549 lung cancer cells. We found that Indomethacine–SN–38 (IndoSN-38) and Naproxen–SN–38(NaproSN-38) as a theranostic prodrug targeting cyclooxygenase-2(COX-2) in cancer cells inhibited A549 cell viability in a dose-dependent fashion. IndoSN-38 and NaproSN-38 inhibited A549 cell viability in a dose-dependent fashion. The suppression of A549 cell viability was due to induction of the cell apoptosis by enhancing the activities of Caspase 3 and Caspase 8. The cell cycle arrest of sub-G1 was found in the cells treated with IndoSN-38 or NaproSN-38. Collectively, these data suggested that the anti-proliferative activities of the NSAID-conjugated SN-38 prodrugs were due to promotion of cell death and arresting the cell cycle which was similar with those of SN-38.

Design, Synthesis, and Evaluation of Glucose Transporter Inhibitor-SN38 Conjugates for Targeting Colorectal Cancer.

Irinotecan (1), a prodrug of SN38 (2) approved by the US Food and Drug Administration for treating colorectal cancer, lacks specificity and causes many side effects. To increase the selectivity and therapeutic efficacy of this drug, we designed and synthesized conjugates of SN38 and glucose transporter inhibitors (phlorizin (5) or phloretin (6)), which could be hydrolyzed by glutathione or cathepsin to release SN38 in the tumor microenvironment, as a proof of concept. These conjugates (8, 9, and 10) displayed better antitumor efficacy with lower systemic exposure to SN38 in an orthotopic colorectal cancer mouse model compared with irinotecan at the same dosage. Further, no major adverse effects of the conjugates were observed during treatment. Biodistribution studies showed that conjugate 10 could induce higher concentrations of free SN38 in tumor tissues than irinotecan at the same dosage. Thus, the developed conjugates exhibit potential for treating colorectal cancer.

Disulfide Bond-Based SN38 Prodrug Nanoassemblies with High Drug Loading and Reduction-Triggered Drug Release for Pancreatic Cancer Therapy.

Chemotherapy is a significant and effective therapeutic strategy that is frequently utilized in the treatment of cancer. Small molecular prodrug-based nanoassemblies (SMPDNAs) combine the benefits of both prodrugs and nanomedicine into a single nanoassembly with high drug loading, increased stability, and improved biocompatibility. In this study, a disulfide bond inserted 7-ethyl-10-hydroxycamptothecin (SN38) prodrug was rationally designed and then used to prepare nanoassemblies (SNSS NAs) that were selectively activated by rich glutathione (GSH) in the tumor site. The characterization of SNSS NAs and the in vitro and in vivo evaluation of their antitumor effect on a pancreatic cancer model were performed. In vitro findings demonstrated that SNSS NAs exhibited GSH-induced SN38 release and cytotoxicity. SNSS NAs have demonstrated a passive targeting effect on tumor tissues, a superior antitumor effect compared to irinotecan (CPT-11), and satisfactory biocompatibility with double dosage treatment. The SNSS NAs developed in this study provide a new method for the preparation of SN38-based nano-delivery systems with improved antitumor effect and biosafety.

Smart stimuli-responsive carrier-free nanoassembly of SN38 prodrug as efficient chemotherapeutic nanomedicine

The compound 7-ethyl-10-hydroxy-camptothecin (SN38) is a broad-spectrum antitumor agent whose applications are greatly limited by its poor solubility. Therefore, irinotecan, the hydrophilic derived prodrug of SN38, has been developed as the commercial formulation Campto® for colorectal cancer. However, only 1% to 0.1% of irinotecan is converted to active SN38 in vivo, thus leading to unsatisfactory antitumor activity in clinical settings. Herein, we report a smart stimuli-responsive SN38 prodrug nanoassembly for efficient cancer therapy. First, SN38 was conjugated with an endogenous lipid, cholesterol (CST), via a redox dual-responsive disulfide bond (namely SN38-SS-CST). The prodrug self-assembled into uniform prodrug nanoassemblies with good colloidal stability and ultrahigh drug loading. SN38-SS-CST NPs released sufficient SN38 in the redox environments of tumor cells but remained intact in normal tissues. Finally, SN38-SS-CST NPs potently inhibited the growth of colon cancer without causing systemic toxicity, thus indicating their promise as a translational chemotherapeutic nanomedicine.

Induction of Immune Responses and Phosphatidylserine Exposure by TLR9 Activation Results in a Cooperative Antitumor Effect with a Phosphatidylserine-targeting Prodrug.

Head and neck cancer is a major cancer type, with high motility rates that reduce the quality of life of patients. Herein, we investigated the effectiveness and mechanism of a combination therapy involving TLR9 activator (CpG-2722) and phosphatidylserine (PS)-targeting prodrug of SN38 (BPRDP056) in a syngeneic orthotopic head and neck cancer animal model. The results showed a cooperative antitumor effect of CpG-2722 and BPRDP056 owing to their distinct and complementary antitumor functions. CpG-2722 induced antitumor immune responses, including dendritic cell maturation, cytokine production, and immune cell accumulation in tumors, whereas BPRDP056 directly exerted cytotoxicity toward cancer cells. We also discovered a novel function and mechanism of TLR9 activation, which increased PS exposure on cancer cells, thereby attracting more BPRDP056 to the tumor site for cancer cell killing. Killed cells expose more PS in tumor for BPRDP056 targeting. Tumor antigens released from the dead cells were taken up by antigen-presenting cells, which enhanced the CpG-272-promoted T cell-mediated tumor-killing effect. These form a positive feed-forward antitumor effect between the actions of CpG-2722 and BPRDP056. Thus, the study findings suggest a novel strategy of utilizing the PS-inducing function of TLR9 agonists to develop combinational cancer treatments using PS-targeting drugs.

Novel disulfide bond bridged 7-ethyl-10-hydroxyl camptothecin-undecanoic acid conjugate/human serum albumin nanoparticles for breast cancer therapy.

7-Ethyl-10-hydroxyl camptothecin (SN38), a semisynthetic derivative of camptothecin, exhibited extreme pharmacological activities in treating a range of cancers. However, its poor aqueous solubility and low stability hinder its clinical applications. Hence, a redox-responsive SN38 prodrug encapsulated human serum albumin (HSA) nanoparticle is developed to realize its potential in the clinic. First, a disulfide bond bridged 7-ethyl-10-hydroxyl camptothecin-undecanoic acid conjugate (SN38-SS-COOH) was synthesized and characterized structurally. After that, SN38-SS-COOH/HSA nanoparticles (SNH NPs) were prepared by the desolvation method. The SNH NPs with a feed molar ratio of 9 : 1 of SN38-SS-COOH : HSA showed a spherical structure with a diameter range of approximately 120-150 nm revealed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Fluorescence quenching confirmed the formation of SNH NP complexes by dual hydrophobic force and electrostatic interaction. The SNH NPs have a high drug loading of 10.44% and an encapsulation efficiency of 89.59% with good stability. Moreover, the redox responsiveness was validated by glutathione (GSH)-triggered accelerated release of parent drug SN38. In an in vivo pharmacokinetic study, the SNH NPs exhibited a significantly prolonged circulation time (t1/2, 3.77-fold) compared with free SN38. Finally, the in vivo antitumor efficacy and systemic toxicity of SNH NPs in a breast xenograft model were thoroughly evaluated. The inhibition rate of tumor growth induced by the SNH NPs reached 70.1%, while only 50.1% was achieved for irinotecan at an equivalent SN38 dosage of 10 mg kg-1. More importantly, the SNH NPs achieved a higher level of tumor growth inhibition (85.3%) by increasing the dosage to 60 mg kg-1 SN38 without obvious adverse effects. Taken together, the use of redox-responsive SN38 prodrug/HSA NPs could be a promising strategy to deliver highly active SN38 for breast cancer chemotherapy.

Two-Stage SN38 Release from a Core-Shell Nanoparticle Enhances Tumor Deposition and Antitumor Efficacy for Synergistic Combination with Immune Checkpoint Blockade.

Long-circulating nanomedicines efficiently deliver chemotherapies to tumors to reduce general toxicity. However, extended blood circulation of nanomedicines can increase drug exposure to leukocytes and lead to hematological toxicity. Here, we report a two-stage release strategy to enhance the drug deposition and antitumor efficacy of OxPt/SN38 core-shell nanoparticles with a hydrophilic oxaliplatin (OxPt) prodrug coordination polymer core and a lipid shell containing a hydrophobic cholesterol-conjugated SN38 prodrug (Chol-SN38). By conjugating cholesterol to the phenol group of SN38 via an acetal linkage and protecting the 20-hydroxy position with a trimethylsilyl (TMS) group, Chol-SN38 releases SN38 in two stages via esterase-catalyzed cleavage of the acetal linkage in the liver followed by acid-mediated hydrolysis of the TMS group to preferentially release SN38 in tumors. Compared to irinotecan, OxPt/SN38 reduces SN38 blood exposure by 9.0 times and increases SN38 tumor exposure by 4.7 times. As a result, OxPt/SN38 inhibits tumor growth on subcutaneous, spontaneous, and metastatic tumor models by causing apoptotic and immunogenic cell death. OxPt/SN38 exhibits strong synergy with the immune checkpoint blockade to regress subcutaneous colorectal and pancreatic tumors with 33-50% cure rates and greatly inhibits tumor growth and invasion in a spontaneous prostate cancer model and a liver metastasis model of colorectal cancer without causing side effects. Mechanistic studies revealed important roles of enhanced immunogenic cell death and upregulated PD-L1 expression by OxPt/SN38 in activating the tumor immune microenvironment to elicit potent antitumor immunity. This work highlights the potential of combining innovative prodrug design and nanomedicine formulation to address unmet needs in cancer therapy.

Pulmonary delivery of liposomes co-loaded with SN38 prodrug and curcumin for the treatment of lung cancer

A co-delivery system of SN38 (7-ethyl-10-hydroxyl camptothecin) prodrug and CUR (curcumin) was designed for the treatment of lung cancer by pulmonary delivery. SN38 was linked to cell-penetrating peptide (CPP) TAT via a polyethylene glycol (PEG) linker to form the SN38 prodrug (TAT-PEG-SN38). Liposomes co-loaded with amphiphilic TAT-PEG-SN38 and curcumin (Lip-TAT-PEG-SN38/CUR) were successfully prepared by a microfluidic method for the treatment of lung cancer via pulmonary delivery. Lip-TAT-PEG-SN38/CUR showed nanometer-sized sphericity and a particle size of 171.21 nm. Besides, Lip-TAT-PEG-SN38/CUR exhibited enhanced antiproliferative effect, increased cell apoptosis induction and improved cell cycle arrest compared to the single agents in vitro. The combination induced significant tumor inhibition in a BALB/c mouse lung cancer model. These results indicated that our SN38 prodrug and curcumin co-delivery system was a promising candidate for lung cancer treatment.

The effect of AS1411 aptamer on anti-tumor effects of dendrimers containing SN38

ObjectiveAlthough 7-Ethyl-10-hydroxy-camptothecin (SN38) is the most physiologically active of the camptothecin, its application has been limited due to its poor solubility in pharmaceutical solvents. Irinotecan is a prodrug of SN38 and the only commercially available formulation of this group. However, due to individual differences, the metabolism rate of Irinotecan to SN38 varies from person to person. In this study, we investigated the effect of aptamer functionalization on therapeutic efficiency of PAMAM dendrimers containing SN38. Methods and materialsAS1411 aptamer conjugated PEGylated PAMAM containing SN38 was prepared and characterized for drug loading and PEGylation efficiency. In vitro cytotoxicity and cellular uptake of SN38 in prepared formulations after 3 h of exposure to murine colon carcinoma (C26) cell line were investigated. Then in vivo anti-tumor efficacy and survival analysis were studied in C26 mice bearing tumor for 54 days. ResultsIn vitro evaluations revealed significantly higher cytotoxicity and much lower IC50 for all preparations compared to SN38 solution. Cellular uptake studies showed a higher value of uptake for aptamer conjugated formulations after 3 h of exposure. Regarding in vivo results, all prepared formulations improved survival of animal model. All PEGylated formulations conjugated with aptamer in dose of 1 mg/kg and 2 mg/kg and formulation conjugated with aptamer in dose of 2 mg/kg indicated significantly better tumor growth inhibition compared to Irinotecan (25 mg/kg). ConclusionThe results of this study showed that encapsulation of SN38 in dendrimer and modification of dendrimer by A1411 aptamer improved the anti-tumor effect of drug.

Tumor-Activatable Nanoparticles Target Low-Density Lipoprotein Receptor to Enhance Drug Delivery and Antitumor Efficacy.

The binding of plasma proteins to nanomedicines is widely considered detrimental to their delivery to tumors. Here, the design of OxPt/SN38 nanoparticle containing a hydrophilic oxaliplatin (OxPt) prodrug in a coordination polymer core and a hydrophobic cholesterol‐conjugated SN38 prodrug on the lipid shell for active tumor targeting is reported. OxPt/SN38 hitchhikes on low‐density lipoprotein (LDL) particles, concentrates in tumors via LDL receptor‐mediated endocytosis, and selectively releases SN38 and OxPt in acidic, esterase‐rich, and reducing tumor microenvironments, leading to 6.0‐ and 4.9‐times higher accumulations in tumors over free drugs. By simultaneously crosslinking DNA and inhibiting topoisomerase I, OxPt/SN38 achieved 92–98% tumor growth inhibition in five colorectal cancer tumor models and prolonged mouse survival by 58–80 days compared to free drug controls in three human colorectal cancer tumor models without causing serious side effects. The study has uncovered a novel nanomedicine strategy to co‐deliver combination chemotherapies to tumors via active targeting of the LDL receptor.

A High-Content Screen for C/EBPα Expression Identifies Novel Therapeutic Agents in Dedifferentiated Liposarcoma.

Dedifferentiated liposarcoma (DDLS), one of the most common and aggressive sarcomas, infrequently responds to chemotherapy. DDLS survival and growth depend on underexpression of C/EBPα, a tumor suppressor and transcriptional regulator controlling adipogenesis. We sought to screen and prioritize candidate drugs that increase C/EBPα expression and may therefore serve as differentiation-based therapies for DDLS. We screened known bioactive compounds for the ability to restore C/EBPα expression and inhibit proliferation selectively in two DDLS cell lines but not in normal adipose-derived stem cells (ASC). Selected hits' activity was validated, and the mechanism of the most potent, SN-38, was investigated. The in vivo efficacy of irinotecan, the prodrug of SN-38, was evaluated in DDLS xenograft models. Of 3,119 compounds, screen criteria were met by 19. Validation experiments confirmed the DDLS selectivity of deguelin, emetine, and SN-38 and showed that they induce apoptosis in DDLS cells. SN-38 had the lowest IC50 (approximately 10 nmol/L), and its pro-apoptotic effects were countered by knockdown of CEBPA but not of TP53. Irinotecan significantly inhibited tumor growth at well-tolerated doses, induced nuclear expression of C/EBPα, and inhibited HIF1α expression in DDLS patient-derived and cancer cell line xenograft models. In contrast, doxorubicin, the most common treatment for nonresectable DDLS, reduced tumor growth by 30% to 50% at a dose that caused weight loss. This high-content screen revealed potential treatments for DDLS. These include irinotecan, which induces apoptosis of DDLS cells in a C/EBPα-dependent, p53-independent manner, and should be clinically evaluated in patients with advanced DDLS.