Free CDDP Research Articles

Improved efficacy of cisplatin delivery by peanut agglutinin‑modified liposomes in non‑small cell lung cancer.

Globally, non‑small cell lung cancer (NSCLC) is a significant threat to human health, and constitutes >80% of lung cancer cases. Cisplatin (CDDP), a commonly used drug in clinical treatment, has been the focus of research aiming to mitigate its potent toxicity through encapsulation within liposomes. However, challenges, such as a reduced drug loading efficiency and nonspecific release, have emerged as obstacles. The present study aimed to improve the encapsulation efficiency of CDDP within liposomes by pre‑preparation of CDDP and modifying the liposome surface through the incorporation of peanut agglutinin (PNA) as a ligand [CDDP‑loaded PNA‑modified liposomes (CDDP‑PNA‑Lip)]. This strategy was designed to enhance the delivery of CDDP to tumour tissues, thereby reducing associated side effects. The effect of CDDP‑PNA‑Lip on the proliferation and migration of NSCLC cell lines with high MUC1 expression was elucidated through in vitro studies. Additionally, the capacity of PNA modification to augment the targeted anti‑tumour efficacy of liposomes was assessed through xenograft tumour experiments. The results indicated that in an in vitro uptake assay Rhodamine B (RhB)‑loaded PNA‑modified liposomes were taken up by cells with ~50% higher efficiency compared with free RhB. In addition, CDDP‑PNA‑Lip resulted in a 2.65‑fold enhancement of tumour suppression in vivo compared with free CDDP. These findings suggested that the encapsulation of CDDP within ligand‑modified liposomes may significantly improve its tumour‑targeting capabilities, providing valuable insights for clinical drug development.

Carbon nanotubes conjugated with cisplatin activate different apoptosis signaling pathways in 2D and 3D-spheroid triple-negative breast cancer cell cultures: a comparative study

The type of experimental model for the in vitro testing of drug formulations efficiency represents an important tool in cancer biology, with great attention being granted to three-dimensional (3D) cultures as these offer a closer approximation of the clinical sensitivity of drugs. In this study, the effects induced by carboxyl-functionalized single-walled carbon nanotubes complexed with cisplatin (SWCNT–COOH–CDDP) and free components (SWCNT–COOH and CDDP) were compared between conventional 2D- and 3D-spheroid cultures of human breast cancer cells. The 2D and 3D breast cancer cultures were exposed to various doses of SWCNT–COOH (0.25–2 μg/mL), CDDP (0.158–1.26 μg/mL) and the same doses of SWNCT–COOH–CDDP complex for 24 and 48 h. The anti-tumor activity, including modulation of cell viability, oxidative stress, proliferation, apoptosis, and invasion potential, was explored by spectrophotometric and fluorometric methods, immunoblotting, optical and fluorescence microscopy. The SWCNT–COOH–CDDP complex proved to have high anti-cancer efficiency on 2D and 3D cultures by inhibiting cell proliferation and activating cell death. A dose of 0.632 μg/mL complex triggered different pathways of apoptosis in 2D and 3D cultures, by intrinsic, extrinsic, and reticulum endoplasmic pathways. Overall, the 2D cultures showed higher susceptibility to the action of complex compared to 3D cultures and SWCNT–COOH–CDDP proved enhanced anti-tumoral activity compared to free CDDP.

Structure-Guided Design of Ferritin-Platinum Prodrugs for Targeted Therapy of Esophageal Squamous Cell Carcinoma.

Due to its intrinsic tumor-targeting attribute, limited immunogenicity, and cage architecture, ferritin emerges as a highly promising nanocarrier for targeted drug delivery. In the effort to develop ferritin cage-encapsulated cisplatin (CDDP) as a therapeutic agent, we found unexpectedly that the encapsulation led to inactivation of the drug. Guided by the structural information, we deciphered the interactions between ferritin cages and CDDP, and we proposed a potential mechanism responsible for attenuating the antitumor efficacy of CDDP encapsulated within the cage. Six platinum prodrugs were then designed to avoid the inactivation. The antitumor activities of these ferritin-platinum prodrug complexes were then evaluated in cells of esophageal squamous cell carcinoma (ESCC). Compared with free CDDP, the complexes were more effective in delivering and retaining platinum in the cells, leading to increased DNA damage and enhanced cytotoxic action. They also exhibited improved pharmacokinetics and stronger antitumor activities in mice bearing ESCC cell-derived xenografts as well as patient-derived xenografts. The successful encapsulation also illustrates the critical significance of comprehending the interactions between small molecular drugs and ferritin cages for the development of precision-engineered nanocarriers.

NIR Responsive Drug Cocktail Using J‐Aggregates of Indocyanine Green Loaded Polydopamine Nanoparticles for Chemo‐Phototherapy of Cancer

AbstractCo‐loading of drugs/dyes onto nanoparticles is a widely adapted strategy to achieve synergistic/combinatorial effects. However, one of the co‐loaded drugs may show dominant loading which reduces the loading efficiency of the other depending on the properties of the drug/dye loaded. Cisplatin (CDDP), a potent chemotherapeutic drug has very limited usage because of its poor aqueous solubility and systemic toxicity. A novel J‐aggregate is formulated using indocyanine green (ICG) and CDDP called the ICG J‐aggregate (IJA) which coordinates CDDP with ICG and enhances its water solubility resulting in higher loading. Further, polydopamine nanoparticles (PDA NPs) are used, which has shown excellent loading efficiency of IJA to form P‐IJA nano formulation. The results for the first time provide evidence of 2–4 folds increase in CDDP's loading in IJA formulation in comparison to loading of free CDDP under the same conditions. The overall P‐IJA formulation is capable of multi‐modal cancer therapy, i.e., chemotherapy, photothermal therapy, photodynamic therapy, and ferroptosis‐like selective cancer killing. The formulated P‐IJA is also found to be biocompatible, hemocompatible, and stable. The finding of the study suggests that P‐IJA can be effectively activated under NIR laser/pH as stimuli for deep‐tissue synergistic therapy.

Redox/pH-responsive hollow manganese dioxide nanoparticles for thyroid cancer treatment.

The nano drug delivery system MnO2/CDDP@PDA-Cy5.5 was synthesized in this study to increase the efficacy of Cisplatin (CDDP) on thyroid cancer and alleviate the damage to normal tissue, with the aim of enhancing the anti-cancer efficacy, increasing the drug load, optimizing the control of drug release, and alleviating the systemic toxicity arising from drug off-target. On that basis, high efficacy and low toxicity win-win can be obtained. In this study, hollow manganese dioxide nanoparticles (MnO2 NPs) were prepared based on the template method. CDDP was loaded into the hollow cavity and then modified with polydopamine (PDA) and Cy5.5, with the aim of obtaining the nano-drug loading system MnO2/CDDP@PDA-Cy5.5 NPs. The NPs precisely delivered drugs by intelligently responding to the tumor microenvironment (TME). As indicated by the release curves, the NPs release CDDP rapidly by inducing the decomposition of PDA and MnO2 under acidic or redox conditions, and Magnetic resonance imaging (MRI) contrast agent Mn2+ was generated. The results of the in vivo MRI studies suggested that T1 contrast at the tumor site was notably enhanced under the Enhanced permeability and retention (EPR) effect. After the intravenous administration, the effective tumor accumulation exhibited by the NPs was confirmed by magnetic resonance imaging as a function of time. Compared with free CDDP, the in vivo therapeutic effect was remarkably increased. As indicated by the above-described results, MnO2/CDDP@PDA-Cy5.5 NPs is a drug delivery system exhibiting diagnostic and therapeutic functions.

Cisplatin-Loaded Thermosensitive Liposomes Functionalized with Hyaluronic Acid: Cytotoxicity and In Vivo Acute Toxicity Evaluation

Cisplatin (CDDP) is a potent antitumor drug used in first-line chemotherapy against several solid tumors, including breast cancer. However, toxicities and drug resistance limit its clinical application. Thermosensitive liposome (TSL) functionalized with hyaluronic acid (HA) containing cisplatin (TSL-CDDP-HA) was developed by our research group aiming to promote the release of CDDP in the tumor region under hyperthermia conditions, as well as to decrease toxicity. Thus, this study aimed to evaluate this new formulation (HA-coated TSL-CDDP) concerning in vitro behavior and in vivo toxicity compared to non-coated TSL-CDDP and free CDDP. Cytotoxicity assays and nuclear morphology were carried out against triple-negative breast cancer cells (MDA-MB-231), while an in vivo toxicity study was performed using healthy Swiss mice. The results showed an increase (around 3-fold) in cytotoxicity of the cationic formulation (non-coated TSL-CDDP) compared to free CDDP. On the other hand, TSL-CDDP treatment induced the appearance of 2.5-fold more senescent cells with alteration of nuclear morphology than the free drug after hyperthermia condition. Furthermore, the association of liposomal formulations treatment with hyperthermia increased the percentage of apoptotic cells compared to those without heating. The percentage of apoptotic cells was 1.7-fold higher for TSL-CDDP-HA than for TSL-CDDP. For the in vivo toxicity data, the TSL-CDDP treatment was also toxic to healthy cells, inducing nephrotoxicity with a significant increase in urea levels compared to the saline control group (73.1 ± 2.4 vs. 49.2 ± 2.8 mg/mL). On the other hand, the HA-coated TSL-CDDP eliminated the damages related to the use of CDDP since the animals did not show changes in hematological and biochemical examinations and histological analyses. Thus, data suggest that this new formulation is a potential candidate for the intravenous therapy of solid tumors.

Hyaluronic Acid-Modified Cisplatin-Encapsulated Poly(Lactic-co-Glycolic Acid) Magnetic Nanoparticles for Dual-Targeted NIR-Responsive Chemo-Photothermal Combination Cancer Therapy.

Combination chemo-photothermal therapy with nanomaterials can reduce the dose of chemotherapeutic drugs required for effective cancer treatment by minimizing toxic side effects while improving survival times. Toward this end, we prepare hyaluronic acid (HA)-modified poly(lactic-co-glycolic acid) (PLGA) magnetic nanoparticles (MNP) for the CD44 receptor-mediated and magnetic field-guided dual-targeted delivery of cisplatin (CDDP). By co-encapsulating the CDDP and oleic acid-coated iron oxide MNP (IOMNP) in PLGA, the PMNPc was first prepared in a single emulsification/solvent evaporation step and successively surface modified with chitosan and HA to prepare the HA/PMNPc. Spherical HA/PMNPc nanoparticles of ~300 nm diameter can be prepared with 18 and 10% (w/w) loading content of CDDP and IOMNP and a pH-sensitive drug release to facilitate the endosomal release of the CDDP after intracellular uptake. This leads to the higher cytotoxicity of the HA/PMNPc toward the U87 glioblastoma cells than free CDDP with reduced IC50, a higher cell apoptosis rate, and the enhanced expression of cell apoptosis marker proteins. Furthermore, the nanoparticles show the hyperthermia effect toward U87 after short-term near-infrared (NIR) light exposure, which can further elevate the cell apoptosis/necrosis rate and upregulate the HSP70 protein expression due to the photothermal effects. The combined cancer therapeutic efficacy was studied in vivo using subcutaneously implanted U87 cells in nude mice. By using dual-targeted chemo-photothermal combination cancer therapy, the intravenously injected HA/PMNPc under magnetic field guidance and followed by NIR laser irradiation was demonstrated to be the most effective treatment modality by inhibiting the tumor growth and prolonging the survival time of the tumor-bearing nude mice.

A Simple Preparation Method of Gelatin Hydrogels Incorporating Cisplatin for Sustained Release.

The objective of this study was to develop a new preparation method for cisplatin (CDDP)-incorporated gelatin hydrogels without using chemical crosslinking nor a vacuum heating instrument for dehydrothermal crosslinking. By simply mixing CDDP and gelatin, CDDP-crosslinked gelatin hydrogels (CCGH) were prepared. CDDP functions as a crosslinking agent of gelatin to form the gelatin hydrogel. Simultaneously, CDDP is incorporated into the gelatin hydrogel as a controlled release carrier. CDDP's in vitro and in vivo anticancer efficacy after incorporation into CCGH was evaluated. In the in vitro system, the CDDP was released gradually due to CCGH degradation with an initial burst release of approximately 16%. CDDP metal-coordinated with the degraded fragment of gelatin was released from CCGH with maintaining the anticancer activity. After intraperitoneal administration of CCGH, CDDP was detected in the blood circulation while its toxicity was low. Following intraperitoneal administration of CCGH in a murine peritoneal dissemination model of human gastric cancer MKN45-Luc cell line, the survival time was significantly prolonged compared with free CDDP solution. It is concluded that CCGH prepared by the CDDP-based crosslinking of gelatin is an excellent sustained release system of CDDP to achieve superior anticancer effects with minimal side effects compared with free CDDP solution.

Cisplatin Nanoparticles Promote Intratumoral CD8+ T Cell Priming via Antigen Presentation and T Cell Receptor Crosstalk.

Nanomedicines are highly promising for cancer therapy due to their minimal side effects. However, little is known regarding their host immune response, which may limit their clinical efficacy and applications. Here, we find that cisplatin (CDDP)-loaded poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol) complex nanoparticles (CDDP-NPs) elicit a strong antitumor CD8+ T cell-mediated immune response in a tumor-bearing mouse model compared to free CDDP. Mechanistically, the sustained retention of CDDP-NPs results in persistent tumor MHC-I overexpression, which promotes the formation of MHC-I-antigen peptide complex (pMHC-I), enhances the interaction between pMHC-I and T cell receptor (TCR), and leads to the activation of TCR signaling pathway and CD8+ T cell-mediated immune response. Furthermore, CDDP-NPs upregulate the costimulatory OX40 on intratumoral CD8+ T cells, and synergize with the agonistic OX40 antibody (aOX40) to suppress tumor growth by 89.2%. Our study provides a basis for the efficacy advantage of CDDP-based nanomedicines and immunotherapy.

Biocompatibility study of P (N-isopropylacrylamide)-based nanocomposite and its cytotoxic effect on HeLa cells as a drug delivery system for Cisplatin

Cisplatin (CDDP) is widely used as an effective drug in the treatment of various cancers. In spite of its therapeutic effects, there are disadvantages in using CDDP, including causing toxicity in healthy cells, also tumor cells become resistant in prolonged use. The use of magnetic nanogels (nanocomposite), as a drug delivery system, can be a potential strategy to overcome these disadvantages. In this study, the biocompatibility (hemocompatibility and cytocompatibility) of the magnetic, pH, and thermo-responsive poly (N-isopropylacrylamide-co-N, N-dimethylaminoethyl methacrylate-co-4-acrylamidofluorescein)-Fe3O4 nanocomposite was assessed in normal cells. Moreover, we evaluated the cytotoxicity, apoptosis, and drug-resistant genes expression of CDDP-loaded nanocomposite against free CDDP in the cervical cancer cell line (HeLa cells) to investigate its potentials as a vector for drug delivery. The results exhibited that the prepared nanocomposite had an appropriate hemocompatibility. Also, the nanocomposite displayed a good cytocompatibility using LDH test. In addition, the MTT assay of the blank nanocomposite, free CDDP, and CDDP-loaded nanocomposite in the HeLa cells indicated that the blank nanocomposite, had no cytotoxic effects on the cells. However, the Free CDDP and CDDP-loaded nanocomposites demonstrated considerable amount of cytotoxicity effect on the HeLa cells (p < 0.05). The results from the Real Time PCR illustrated that the CDDP-loaded nanocomposite could increase the expression of apoptosis genes and reduce the expression of drug resistance genes in the cancer cells. Our data suggested that the synthetized nanocomposite could be used as an effective and biocompatible drug delivery system for smart delivery and intravenous administration of CDDP. Literature mining-based network discovery proposed candidates for tumor sensitivity/resistance to Cisplatin, viz NR4A1, NR1I2, TP73, and TP53 transcription factors as well as EDN1, CD40LG, INS, and TNFSF11 secreted ligands.

Cisplatin-Chelated Iminodiacetic Acid-Conjugated Hyaluronic Acid Nanogels for the Treatment of Malignant Pleural Mesothelioma in Mice.

Malignant pleural mesothelioma (MPM) is one of the intractable cancers that require a more effective therapeutic strategy for clinical practice. Hyaluronic acid (HA) nanogels were prepared by the chelation of cisplatin (CDDP) with different molecular weights of iminodiacetic acid-conjugated hyaluronic acid (HA-IDA). The sizes of the 100, 850, and 2000 kDa HA nanogels were 33, 43, and 44 nm, respectively. MSTO-211H, a human MPM cell line, was more effective in taking up all three HA nanogels compared to AB22, a mouse MPM cell line. In addition, the 850 kDa HA nanogel showed higher anticancer activity against AB22 and MSTO-211H than 100 and 2000 kDa HA nanogels. Furthermore, all the HA nanogels showed a milder cytotoxic effect on normal Met-5A mesothelial cells compared to that exhibited by free CDDP. Finally, the 850 kDa HA nanogel was administrated intrapleurally into both the MSTO-211H xenograft and AB22 allograft mouse models of MPM using an injectable HA-based hydrogel. HA nanogels showed a significant therapeutic effect in both the xenograft and allograft models.

One-Pot Preparation of Ultra-Small Lipid-Polymer Nanoparticles Loaded with Cis-Platinum to Combat Lung Cancer

The cis-platinum (CDDP) is a first line chemotherapeutics drugs to combat lung cancer. However, its efficacy is largely limited due to the off-target delivery and multidrug resistance (MDR) upon in vivo applications. In order to solve this problem, here in our study, we prepared ultra-small lipidpolymer nanoparticles (USLPNPs) using one-pot method and to load CDDP (USLPNPs-CDDP) for the effective lung cancer therapy. Our results showed that the size of USLPNPs-CDDP was 20 nm and the stability of this platform was high. The sustained drug release afforded the long-lasting administration of CDDP to treat cancers. Most importantly, the USLPNPs-CDDP was able to bypass the CDDP resistance of A549/CDDP cells, which resulted in better anticancer benefits as compared to free CDDP both in vitro and in vivo.

The effect of free and encapsulated cisplatin into long-circulating and pH-sensitive liposomes on IEC-6 cells during wound healing in the presence of host-microbiota.

To circumvent cisplatin (CDDP) toxic effects and improve the antitumoural effect, our research group developed long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP). This study aimed to evaluate whether SpHL-CDDP is associated with intestinal protection under in-vitro conditions in the presence of host-microbiota, compared with free CDDP. The cytotoxicity of CDDP and SpHL-CDDP were evaluated by colorimetric MTT and sulforhodamine B (SRB) assays. Epithelial proliferation was assessed by using an in-vitro wounding model in the presence of host-microbiota with intestinal epithelial cell line 6 (IEC-6) monolayers. Cytokines were determined by ELISA. Reduced cytotoxicity of SpHL-CDDP in IEC-6 cells (minimum of 1.3-fold according to the IC50 values) was observed when compared with CDDP. The presence of microbiota or CDDP reduced the wound healing. The association of microbiota and SpHL-CDDP improved the wound healing and cell number in IEC-6 cells when compared with control. These beneficial results can be associated with increased IL-6 and IL-10 levels induced by SpHL-CDDP which were affected by the presence of microbiota. These results indicate that the presence of microbiota associated with SpHL-CDDP provided less intestinal cellular damages compared with CDDP and constitutes a promising candidate for clinical use.

Pheophorbide co-encapsulated with Cisplatin in folate-decorated PLGA nanoparticles to treat nasopharyngeal carcinoma: Combination of chemotherapy and photodynamic therapy

The adverse effect and drug resistance of Cisplatin (CDDP) could be potential reduced by delivering in targeted nanoparticles and by combining with adjuvant therapy such as photodynamic therapy. In this study, F/CDPR-NP was formulated and characterized for all the physicochemical, biological and in vivo analysis. The results obtained from various in vitro and biological studies showed that encapsulation of CDDP and PBR in PLGA nanoparticles results in controlled release of encapsulated drugs and exhibited significantly low cell viability in CNE-1 and HNE-1 cancer cells. F/CDPR-NP significantly prolonged the blood circulation of the encapsulated drugs. The AUC of CDDP from F/CDPR-NP (4-fold) was significantly higher compared to that of free CDDP and similarly significantly higher t1/2 for CDDP from F/CDPR-NP was observed. F/CDPR-NP in the presence of laser irradiation showed significant reduction in the tumor burden with low tumor cell proliferations compared to either CDPR-NP or free CDDP indicating the potential of targeted nanoparticles and photodynamic therapy. Overall, combination of treatment modalities and active targeting approach paved way for the higher antitumor activity in nasopharyngeal carcinoma model. The positive results from this study will show new horizon for the treatment of other cancer models.

A Novel Formulation of Cisplatin with γ-Polyglutamic Acid and Chitosan Reduces Its Adverse Renal Effects: An In Vitro and In Vivo Animal Study.

Cisplatin (cis-diamminedichloroplatinum (II); CDDP) is a key chemotherapeutic agent but causes renal damage and other off-target effects. Here, we describe the pharmacological and biochemical characteristics of a novel formulation of CDDP complexed with γ-polyglutamic acid (γ-PGA) and chitosan (CS), γ-PGA/CDDP-CS, developed by complexing CDDP with γ-PGA, then adding CS (15 kDa; 10 mol%/γ-PGA). We analyzed tumor cytotoxicity in vitro, as well as blood kinetics, acute toxicity, and antitumor efficacy in vivo in BALB/cAJcl mice. γ-PGA/CDDP-CS showed pH-dependent release in vitro over 12 days (9.1% CDDP released at pH 7.4; 49.9% at pH 5.5). It showed in vitro cytotoxicity in a dose-dependent manner similar to that of uncomplexed CDDP. In a mesothelioma-bearing mouse model, a 15 mg/kg dose of CDDP inhibited tumor growth regardless of the type of formulation, complexed or uncomplexed; however, all mice in the uncomplexed CDDP group died within 13 days. γ-PGA/CDDP-CS was as effective as free CDDP in vivo but much less toxic.

1H and 195Pt NMR prediction for inclusion compounds formed by cisplatin and oxidized carbon nanostructures.

Prediction of NMR chemical shifts can assist experimentalists in the characterization of drug delivery systems based on carbon nanocomposites. Chemical shifts are strongly correlated to the nucleus position and its chemical neighborhood. Therefore, to predict structures and NMR properties of complex chemical models, choosing a more consistent theoretical level capable of providing more realistic results and moderate computational demand is a major challenge. In this work, we predicted the NMR spectra of inclusion compounds formed by cisplatin (cDDP) and an oxidized carbon nanotube (CNTox) and nanocone (CNCox) considered by specialists as potential drug delivery systems. The 195Pt NMR chemical shifts calculated at the DFT level with the new relativistic NMR-DKH basis set were −2314 ppm and −2192 ppm for cDDP@CNTox and cDDP@CNCox complexes, respectively, which are both high-field shifted relative to the free cDDP (−2110 ppm). 1H NMR chemical shifts are also sensitive to the inclusion process. The H (NH3) signals are found on average at +4.3 (cDDP), −5.1 (cDDP@CNTox) and +6.6 ppm (cDDP@CNCox). Interestingly, despite the similar inclusion modes in CNTox and CNCox cavities, the 1H NMR shifts were in opposite directions. A possible reason might be the higher stability of cDDP@CNTox (ΔEF = −19.9 kcal mol−1) than that of cDDP@CNCox (ΔEF = −5.7 kcal mol−1), which suggests a short guest–host contact in the former and consequently, a more efficient shielding of hydrogen atoms due to the electron-rich carbon structure. These results may be helpful as comparison data in the NMR spectra assignment in solution and the inclusion compounds' structural elucidation.

Polyphenol-cisplatin complexation forming core-shell nanoparticles with improved tumor accumulation and dual-responsive drug release for enhanced cancer chemotherapy

Cisplatin (CDDP) is a potent first-line antitumor drug but suffers severe side effects and poor pharmacokinetics. Its complexation with polycarboxylic acids, such as polyglutamic acids, is generally used to fabricate nanoformulations for CDDP delivery; however, the multiple strong complexations makes intracellular drug release slow. Herein, we report a novel polyphenol-metal coordination method to fabricate CDDP-incorporated core-shell nanoparticles, which are stable in blood circulation but dissociate in the tumor. Methoxyl-PEG terminated with one or two gallic acids (PEG-GA or PEG-GA2) complexed CDDP and produced well-defined nanoparticles (PEG-GAx/Pt) with CDDP loading contents as high as 17.7% to 29.8%. The PEG-GAx/Pt nanoparticles were very stable in the physiological conditions and had slow blood clearance and efficient tumor accumulation, but dissociated quickly and released CDDP in response to the tumor acidity or elevated levels of reactive oxygen species (ROS). PEG-GAx/Pt nanoparticles exhibited improved antitumor efficiency against 4 T1 breast cancer and A549 lung carcinoma with much-reduced toxicity compared to free CDDP. The work demonstrates a new strategy of cisplatin-polyphenol coordination for developing platinum drugs' nanomedicines.

A novel topical treatment for bone metastases using a gelatin hydrogel incorporating cisplatin as a sustained release system.

Management of bone metastasis is becoming increasingly important. Thus, local and systemic treatment options have been developed for control. Although systemic administration of anticancer agents is effective for bone metastasis, it is often stopped because of poor general conditions or side effects. Therefore, it is highly desirable to develop a more effective and safer local treatment for bone metastasis. The purpose of the current study was to investigate the antitumor effects and safety of gelatin hydrogel microspheres incorporating cisplatin (GM-CDDP), which we developed as a sustained release system without harmful substances. First, we assessed GM-CDDP for its in vitro degradability and potential for sustained release. Second, in vivo antitumor and side effects were evaluated using a murine bone metastasis model of MDA-MB-231 human breast cancer cells incorporating GFP. In vitro, initial bursts were observed within 2 h and CDDP was released gradually with gelatin hydrogel degradation, which reached 100% at 48 h. In vivo, local administration of GM-CDDP (2 mg/kg) significantly suppressed tumor growth and bone osteolysis compared with the control, and local and systemic administration of free CDDP (2 mg/kg; p < 0.05). Local administration of GM-CDDP significantly reduced loss of body weight and elevation of blood urea nitrogen compared with the systemic administration of free CDDP (p < .05). The current study suggests that local administration of GM-CDDP achieves higher antitumor effects with a potential for lesser side effects compared with local or systemic administration of free CDDP.

Abstract 6418: Targeting STAT3-driven breast cancer cells using layer-by-layer nanoparticles

Abstract Inappropriate activation of the oncogenic transcription factor STAT3 is a common finding in breast cancer, in which it is constitutively activated in 70% of all cases and almost all triple negative breast cancers (TNBC). We investigated exploiting this feature of breast cancer for the development of tumor-targeting therapy using a novel drug delivery system, layer-by-layer (LbL) nanoparticles (NP). We found that the cellular lipid profile, likely including the plasma membrane, is modulated by the level of STAT3 transcriptional activity. To explore the potential of utilizing this property to specifically target STAT3-driven cancer cells, we screened a library of LbL NPs differing in their surface layer, which modifies their interactivity and cellular internalization. We found that poly-L-glutamic acid (PLE)-coated NPs were taken up by STAT3-transformed mammary epithelial cells to a 50% greater extent than non-transformed cells. This did not reflect a non-specific effect of neoplastic transformation, as LbL NPs coated with other modifications, such as dextran sulfate, showed no difference in uptake. Furthermore, TNBC cell lines, such as MDA-MB-231 and SUM159-PT showed rapid uptake of PLE NPs, which was attenuated by inhibition of STAT3 by RNA interference. We also characterized NP uptake in three-dimensional breast cancer organoids, which may better model behavior in tumor systems. We found that STAT3-transformed organoids grew in structures of notably higher cellular density, yet they were penetrated by PLE NPs more effectively than non-transformed ones. To evaluate the translational potential of these findings, we tested the effect of PLE-coated NPs incorporating the cytotoxic agent cisplatin (CDDP), as platinum agents are used clinically in TNBC. Breast cancer cells characterized by high STAT3 activity, including TNBC, showed significantly less survival when treated with CDDP-loaded PLE NPs, and this effect was lost when STAT3 expression was abrogated. This did not reflect a general increased sensitivity to cell killing, as these cells were more resistant to the effects of free CDDP. Since radiation therapy is widely used in breast cancer treatment, and is known to further alter the plasma membrane lipid composition, we evaluated the effect of radiation on the uptake of PLE NPs. We found that gamma radiation, in a dose-dependent manner, led to enhanced NP uptake in STAT3-driven cancer cells compared to non-transformed counterparts. LbL nanoparticles with a terminal poly-L-glutamic acid layer represent a new class of drug carriers that are preferentially taken up by STAT3-transformed mammary epithelial cells, and may be used synergistically with radiation therapy. These findings provide a promising starting point for the development of targeted approaches to triple negative breast cancers, which currently lack such therapeutic options. Citation Format: Isidora Tošić, Lisa N. Heppler, Susana P. Egusquiaguirre, Natalie Boehnke, Santiago Correa, Daniel Costa, Daphne A. Haas-Kogan, Paula T. Hammond, David A. Frank. Targeting STAT3-driven breast cancer cells using layer-by-layer nanoparticles [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6418.

Prominent Enhancement of Cisplatin Efficacy with Optimized Methoxy Poly(ethylene glycol)-Polycaprolactone Block Copolymeric Nanoparticles.

Chemotherapy has been one of the major standard treatments for a variety of cancers. cis-Dichlorodiamminoplatiunum (II) (cisplatin, CDDP), as one of the anticancer agents, demonstrated excellent efficacy against tumor and has been an indispensable component in chemotherapy, chemoradiation, chemo-molecular targeted therapy and chemo-immunotherapy. However, its therapeutic concentration was limited since its inevitable toxicity. Previously, we have constructed CDDPloaded nanoparticles (NPs) with mixture of poly(ethyleneglycol)-polycaprolactone (PEG-PCL) and polycarprolactone (HOPCL) by a facile method. The most optimal proportion of the two copolymers was selected through a series of physical, chemical, cytological and histological evaluations. In the present study, we explored the mechanisms of NPs and observed the in vivo antitumor effect after administrating CDDP-loaded PEG-PCL NPs. Positron emission tomography as well as computed tomography (PET/CT) were adopted for detecting tumoral metabolic activity. Images from fluorescence microscope revealed superior cellular uptake of CDDP-loaded NPs with rhodamine B aggregated intracellularly in cancer cells. Similar apoptotic rates between free CDDP group and CDDP-loaded NPs group was measured by flow cytometry. Tumor volumes and murine weights confirmed the superiority of CDDP-loaded NPs in therapeutic efficacy as compared with free CDDP. Blood tests showed milder side effects in CDDP-loaded nanoparticle group. PET/CT images illustrated less uptake intensity of FDG in mice received CDDP-loaded NPs than free CDDP. Our results suggest that PEG-PCL/PCL NPs could be a promising antitumor drug carrier for CDDP delivery with solid efficacy and minor side effects.