Free CDDP Research Articles

The role of a drug-loaded poly (lactic co-glycolic acid) (PLGA) copolymer stent in the treatment of ovarian cancer.

Objectives: Cisplatin (CDDP) is a widely used and effective basic chemotherapeutic drug for the treatment of a variety of tumors, including ovarian cancer. However, adverse side effects and acquired drug resistance are observed in the clinical application of CDDP. Identifying a mode of administration that can alleviate side effects and reduce drug resistance has become a promising strategy to solve this problem.Methods: In this study, 3D printing technology was used to prepare a CDDP-poly (lactic-co-glycolic acid) (CDDP-PLGA) polymer compound stent, and its physicochemical properties and cytotoxicity were evaluated both in vitro and in vivo.Results: The CDDP-PLGA stent had a significant effect on cell proliferation and apoptosis and clearly decreased the size of subcutaneous tumors in nude mice, whereas the systemic side effects were mild compared with those of intraperitoneal CDDP injection. Compared with the control group, CDDP-PLGA significantly increased the mRNA and protein levels of p-glycoprotein (P < 0.01; P < 0.01) and decreased vascular endothelial growth factor mRNA (P < 0.05) and protein levels (P < 0.01), however, CDDP-PLGA significantly decreased the mRNA and protein levels of p-glycoprotein (P < 0.01; P < 0.01) and vascular endothelial growth factor (P < 0.01; P < 0.01), which are associated with chemoresistance, in subcutaneous tumor tissue. Immunohistochemistry assay results revealed that, in the CDDP-PLGA group, the staining of the proliferation-related genes Ki67 and PCNA were lightly, and the apoptosis-related gene caspase-3 stained deeply.Conclusions: PLGA biomaterials loaded with CDDP, as compared with the same amount of free CDDP, showed good efficacy in terms of cytotoxicity, as evidenced by changes in apoptosis. Continuous local CDDP release can decrease the systemic side effects of this drug and the occurrence of drug resistance and angiogenesis, and improve the therapeutic effect. This new approach may be an effective strategy for the local treatment of epithelial ovarian cancer.

Abstract 3632: Enhanced efficacy of optimized phenethyl isothiocyanate and cisplatin co-encapsulated liposome nanoparticle for treatment of non-small cell lung cancer

Abstract Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, which is the leading cause of cancer-related death in the United States. Accounting for about 85% of all lung cancers, NSCLC is difficult to treat and its survival rates are low. After decades of basic and clinical research, the most effective treatments still involve the first-generation anticancer agent cisplatin (CDDP) in combination with other drugs. Naturally-occurring compound, phenethyl isothiocyanate (PEITC), can be used to sensitize NSCLC cells to CDDP. We have previously proved that co-encapsulation of PEITC and CDDP in liposomes enhances the cytoxicity toward NSCLC cells, compared to free PEITC or CDDP. In this study, liposomal-PEITC-CDDP is optimized and the release of PEITC and CDDP from the nanoparticle is characterized. In vitro studies show that liposomal-PEITC-CDDP has a higher cytotoxicity toward both A549 and H596 human NSCLC cell lines than toward WI-38 and BEAS-2B human normal lung cell lines. Therfore, we have prepared an efficacious therapy with a potential for fewer side-effects due to low off-target toxicity. Citation Format: Mengwei Sun, Yi Shi, Anthony Di Pasqua. Enhanced efficacy of optimized phenethyl isothiocyanate and cisplatin co-encapsulated liposome nanoparticle for treatment of non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3632.

Intraperitoneal chemotherapy for peritoneal metastases using sustained release formula of cisplatin-incorporated gelatin hydrogel granules.

We previously reported the effectiveness of gelatin microspheres incorporating cisplatin in a mouse model of peritoneal metastases. In this study, we report our new complete sustained-release formula of gelatin hydrogel granules incorporating cisplatin (GHG-CDDP), which exerted a good anti-tumor effect with less toxicity. GHG-CDDP was prepared without organic solvents to enable its future clinical use. The pharmaceutical characterization of GHG-CDDP was performed, and its in vivo degradability was evaluated. The anti-tumor effect was evaluated using a murine peritoneal metastasis model of the human gastric cancer MKN45-Luc cell line. Our new manufacturing process dramatically reduced the initial burst of CDDP release to approximately 2% (wt), while the previous product had a 25-30% initial burst. In intraperitoneal degradation tests, approximately 30% of GHG-CDDP remained in the murine abdominal cavity 7 days after intraperitoneal injection and disappeared within 3 weeks. GHG-CDDP significantly suppressed the in vivo tumor growth (p = 0.02) and prolonged the survival time (p = 0.0012) compared with the control. In contrast, free CDDP did not show a significant therapeutic effect at any dose. Weight loss and hematological toxicity were also significantly ameliorated. GHG-CDDP is a promising treatment option for peritoneal metastases through the complete sustained-release of CDDP with less systemic toxicity.

Targeted Delivery of Cisplatin-Derived Nanoprecursors via a Biomimetic Yeast Microcapsule for Tumor Therapy by the Oral Route.

Targeted therapy via the patient-friendly oral route remains the holy grail of chemotherapy for cancer. Herein we report a yeast-derived platform for targeted oral delivery of cisplatin (CDDP) that is one of the most effective drugs for chemotherapy of various types of cancers.Methods: The optimal conditions were first established to fabricate yeast microcapsules (YCs) with desirable loading capability. Then, CDDP-derived precursor nanoparticles (PreCDDP) were prepared and packaged into YC to produce orally deliverable PreCDDP/YC. The physiochemical properties, in vitro drug release profiles, in vitro antitumor activity, oral targeting capability, in vivo pharmacokinetics, and in vivo efficacy of the YC-based biomimetic delivery system were examined.Results: YCs obtained under the optimized condition showed desirable loading efficiency for quantum dots that were used as a model nanocargo. In vitro experiments demonstrated rapid endocytosis and prolonged retention of YC in macrophages. By electrostatic force-mediated self-deposition, PreCDDP was efficiently loaded into YC. PreCDDP/YC showed potent cytotoxicity in different tumor cells, indicating that PreCDDP loaded in YC maintained its antitumor activity after intracellular release. As compared to CDDP and PreCDDP, orally administered PreCDDP/YC displayed significantly higher bioavailability. Post oral delivery, YC could accumulate in A549 human lung carcinoma xenografts in mice, achieving by monocyte/macrophage-mediated translocation via the lymphatic system. Through this targeting effect, orally administered PreCDDP/YC showed desirable efficacy in A549 xenograft-bearing mice, which was comparable to that of free CDDP administered by intravenous injection. Orally administered free CDDP, however, did not afford antitumor effects. Furthermore, oral treatment with PreCDDP/YC displayed better safety than free CDDP administered via the oral or intravenous route.Conclusions: This biomimetic approach can serve as an effective strategy to develop targeted oral chemotherapies based on CDDP or its derivatives.

Cisplatin Loaded Multiwalled Carbon Nanotubes Induce Resistance in Triple Negative Breast Cancer Cells.

In this paper we developed a method for multiwalled carbon nanotubes (MWCNTs) use as carriers for a drug based on platinum in breast cancer therapy. The method of functionalization involves the carboxyl functionalization of nanotubes and encapsulation of cisplatin (CDDP) into MWCNTs. The biological properties of MWCNTs loaded with CDDP (MWCNT-COOH-CDDP) and of individual components MWCNT-COOH and free CDDP were evaluated on MDA-MB-231 cells. Various concentrations of CDDP (0.316–2.52 µg/mL) and MWCNTs (0.5–4 µg/mL) were applied on cells for 24 and 48 h. Only at high doses of CDDP (1.26 and 2.52 µg/mL) and MWCNT-COOH-CDDP (2 and 4 µg/mL) cell morphological changes were observed. The cellular viability decreased only with approx. 40% after 48 h of exposure to 2.52 µg/mL CDDP and 4 µg/mL MWCNT-COOH-CDDP despite the high reactive oxygen species (ROS) production induced by MWCNTs starting with 24 h. After 48 h, ROS level dropped as a result of the antioxidant defence activation. We also found a significant decrease of caspase-3 and p53 expression after 48 h, accompanied by a down-regulation of NF-κB in cells exposed to MWCNT-COOH-CDDP system which promotes apoptosis escape and thus failing to overcome the triple negative breast cancer (TNBC) cells resistance.

Preparation and Optimization Lipid Nanocapsules to Enhance the Antitumor Efficacy of Cisplatin in Hepatocellular Carcinoma HepG2 Cells.

This work aimed to develop and optimize several lipid nanocapsule formulations (LNCs) to encapsulate cisplatin (CDDP) for treatment of hepatocellular carcinoma. By comparing the effect of oil/surfactant ratio, lecithin content, and oil/surfactant type on LNC characteristics, two LNCs were selected as optimal formulations: HS15-LNC (Solutol HS 15/MCT/lecithin, 54.5:42.5:3%, w/w) and EL-LNC (Cremophor EL/MCT/lecithin, 54.5:42.5:3%, w/w). Both LNCs could effectively encapsulate CDDP with the encapsulation efficiency of 73.48 and 78.84%. In vitro release study showed that both LNCs could sustain the release CDDP. Moreover, cellular uptake study showed that C6-labeled LNCs could be effectively internalized by HepG2 cells. Cellular cytotoxicity study revealed that both LNCs showed negligible cellular toxicity when their concentrations were below 313μg/mL. Importantly, CDDP-loaded LNCs exhibited much stronger cell killing potency than free CDDP, with the IC50 values decreased from 17.93 to 3.53 and 5.16μM after 72-h incubation. In addition, flow cytometric analysis showed that the percentage of apoptotic cells was significantly increased after treatment with LNCs. Therefore, the prepared LNC formulations exhibited promising anti-hepatocarcinoma effect, which could be beneficial to hepatocellular carcinoma therapy.

Co-delivery of cisplatin and CJM-126 via photothermal conversion nanoparticles for enhanced synergistic antitumor efficacy

Polymeric biomaterials that can be smartly disassembled through the cleavage of the covalent bonds in a controllable way upon an environmental stimulus such as pH change, redox, special enzymes, temperature, or ultrasound, as well as light irradiation, but are otherwise stable under normal physiological conditions have attracted great attention in recent decades. The 2-(4-aminophenyl) benzothiazole molecule (CJM-126), as one of the benzothiazole derivatives, has exhibited a synergistic effect with cisplatin (CDDP) and restrains the bioactivities of a series of human breast cancer cell lines. In our study, novel NIR-responsive targeted binary-drug-loaded nanoparticles encapsulating indocyanine green (ICG) dye were prepared as a new co-delivery and combined therapeutic vehicle. The prepared drug-loaded polymeric nanoparticles (TNPs/CDDP-ICG) are stable under normal physiological conditions, while burst drugs release upon NIR laser irradiation in a mild acidic environment. The results further confirmed that the designed co-delivery platform showed higher cytotoxicity than the single free CDDP due to the synergistic treatment of CJM-126 and CDDP in vitro. Taken together, the work might provide a promising approach for effective site-specific antitumor therapy.

Intraperitoneal Delivery of Cisplatin via a Hyaluronan-Based Nanogel/in Situ Cross-Linkable Hydrogel Hybrid System for Peritoneal Dissemination of Gastric Cancer.

Intraperitoneal administration of chemotherapeutics is expected for the treatment of peritoneally disseminated gastric cancer because of poor migration of the drugs from the systemic circulation to the peritoneal cavity. In this study, for intraperitoneal delivery of cisplatin (CDDP), we developed a hyaluronan (HA)-based hybrid system in which CDDP-loaded HA nanogels were either physically encapsulated in or chemically conjugated to injectable HA hydrogels. Physical encapsulation enabled sustained release of HA nanogels from the HA hydrogel matrix for over a week. This was a longer release period than that of encapsulated free CDDP, which released 80% of the drug in 2 days. The longer release was attributed to delayed diffusion of HA nanogels from the hydrogel matrix network. The release profile could be tuned by modifying the chemical conjugation of HA nanogels to the HA hydrogel matrix, as well as the type of chelating ligands used to load CDDP to the nanogel. Furthermore, intraperitoneally administered hybrid had significant antitumor activity in a mouse model of peritoneally disseminated gastric cancer, especially for nodules smaller than 1.0 mm.

Intestinal toxicity evaluation of long-circulating and pH-sensitive liposomes loaded with cisplatin

Cisplatin (CDDP) is a chemotherapeutic agent widely used in several anticancer protocols for instance head and neck, testicle, ovarian, lung and peritoneal carcinomatosis. According to the literature, the use of CDDP is associated with several side effects; among them, we highlighted the mucositis. CDDP, when administered by IP, promoted significant intestinal epithelium alterations in an experimental model. Our research group has proposed that the incorporation of CDDP into long-circulating and pH-sensitive liposomes (SpHL-CDDP) could help to overcome some side effects induced by this drug. Thus, we evaluated signs of intestinal toxicity 24h and 72h after the administration of a single i.p dose of free CDDP or SpHL-CDDP to healthy Swiss mice. Twenty-four hours after administration of free CDDP, the mice showed signs of intestinal toxicity, principally weight loss, increased intestinal permeability associated with a decrease in expression of tight junctions, and histological damage with the presence of inflammatory infiltrates and activation of ERK1/2 and NF-κB. These changes persisted after 72h. While signs of intestinal toxicity were also observed 24h after administration of SpHL-CDDP, after 72h body weight and intestinal permeability of mice in this group were similar to those of mice in the control group. In comparison with the free CDDP treatment group, 72h after treatment mice in the SpHL-CDDP group showed better histological parameters, lower levels of inflammatory infiltrate with increased IL-10 and IgA levels, and less activation of caspase-3, ERK1/2 and NF-κB. These differences could account for the recovery of the intestinal epithelium observed in mice treated with SpHL-CDDP but not in mice treated with free CDDP. In conclusion, here we show that encapsulation of CDDP in SpHL lessens intestinal damage and that, as such, SpHL-CDDP is a promising candidate for clinical use.

A fully absorbable biomimetic polymeric micelle loaded with cisplatin as drug carrier for cancer therapy.

cis-dichlorodiammineplatinum(II) (CDDP)-loaded polymeric micelles for cancer therapy have been developed to reduce the serious side effects of cisplatin CDDP. Herein, polymeric micelles incorporated with cisplatin are prepared based on the complexation between CDDP and hydrophilic poly (L-glutamic acid)-b-poly (2-methacryloyloxyethyl phosphorylcholine) (PLG-b-PMPC) diblock copolymers. These CDDP-loaded micelles possess an average size of 91 nm with narrow distribution, providing remarkable stability in media containing proteins. The release of CDDP from the micelles is faster at pH 5.0 and pH 6.0 than that at pH 7.4 and in a sustained manner without initial burst release. In addition, there is almost no difference in cellular uptake between these CDDP-loaded micelles and free CDDP. Moreover, in vitro cytotoxicity test shows they possess high efficacy to kill 4T1 cells as compared with free drug. Thus, PLG-b-PMPC copolymer might be a promising carrier for CDDP incorporating in cancer therapy.

Co-delivery of polymeric metformin and cisplatin by self-assembled core-membrane nanoparticles to treat non-small cell lung cancer

Clinically, combined therapy of cisplatin (CDDP) and metformin is an effective treatment for non-small cell lung cancer (NSCLC). The success is attributed to synergistic effects between the two drugs. Therefore, we hypothesize that co-encapsulation of CDDP and metformin will avoid the prominent toxicity of CDDP while maintaining the synergy between the regimens. CDDP was first conjugated to polyglutamic acid (PGA) to form anionic PGA-CDDP which was electrostatically complexed with the cationic polymeric metformin (polymet). The nano-sized complex was then stabilized with cationic liposomes composed of DOTAP (2, 3-Dioleoyloxy-propyl)-trimethylammonium/Cholesterol/DSPE-PEG-anisamide aminoethyl. Both in vitro and in vivo experiments confirmed the synergy between polymet and CDDP. CDDP delivered with nanoparticles (NPs) exhibited significantly increased tumor accumulation over free CDDP and suppressed tumor growth through apoptosis in NSCLC H460 tumor-bearing mice without nephrotoxicity. The synergistic effect of polymet alongside CDDP demonstrates that polymet-CDDP NPs can activate the AMP-activated protein kinase α (AMPKα) pathway and inhibit mammalian target rapamycin (mTOR) activity to enhance growth suppression. In all, this platform is the first to successfully co-load polymet, a polymeric metformin, and CDDP into the same nanoparticle for successful treatment of NSCLC.

Cisplatin-crosslinked glutathione-sensitive micelles loaded with doxorubicin for combination and targeted therapy of tumors

The delivery of combination chemotherapy by nanoscale platforms has been demonstrated to enhance cancer treatment in the clinic. Cisplatin (CDDP)-crosslinked, glutathione-sensitive, tumor-targeting micelles based on carboxymethyl chitosan were designed for synergistic cisplatin-doxorubicin (DOX) combination chemotherapy. In our study, DOX was conjugated to carboxymethyl chitosan through a disulfide bond, which was structurally characterized by 1H NMR. The micelles formed by self-assembly were spherical, with the mean diameter of 274nm. The in vitro release studies revealed that the micelles were highly glutathione-sensitive. Cytotoxicity analysis demonstrated that the cisplatin-crosslinked micelles loaded with DOX exhibited enhanced therapeutic efficacy compared with the DOX-loaded nanoparticles, free DOX, and free CDDP. Cellular uptake and intracellular release revealed that the cisplatin-crosslinked micelles loaded with DOX could efficiently deliver and release DOX into the cancer cells. These results clearly indicate that tumor-targeting and glutathione-sensitive micelles provide means for combination drug delivery in cancer treatment.

Functionalized milk-protein-coated magnetic nanoparticles for MRI-monitored targeted therapy of pancreatic cancer.

Engineered nanocarriers have emerged as a promising platform for cancer therapy. However, the therapeutic efficacy is limited by low drug loading efficiency, poor passive targeting to tumors, and severe systemic side effects. Herein, we report a new class of nanoconstructs based on milk protein (casein)-coated magnetic iron oxide (CNIO) nanoparticles for targeted and image-guided pancreatic cancer treatment. The tumor-targeting amino-terminal fragment (ATF) of urokinase plasminogen activator and the antitumor drug cisplatin (CDDP) were engineered on this nanoplatform. High drug loading (~25 wt%) and sustained release at physiological conditions were achieved through the exchange and encapsulation strategy. These ATF-CNIO-CDDP nanoparticles demonstrated actively targeted delivery of CDDP to orthotopic pancreatic tumors in mice. The effective accumulation and distribution of ATF-CNIO-CDDP was evidenced by magnetic resonance imaging, based on the T2-weighted contrast resulting from the specific accumulation of ATF-CNIO-CDDP in the tumor. Actively targeted delivery of ATF-CNIO-CDDP led to improved therapeutic efficacy in comparison with free CDDP and nontargeted CNIO-CDDP treatment. Meanwhile, less systemic side effects were observed in the nanocarrier-treated groups than that in the group treated with free CDDP. Hematoxylin and Eosin and Sirius Red staining of tumor sections revealed the possible disruption of stroma during the treatment with ATF-CNIO-CDDP. Overall, our results suggest that ATF-CNIO-CDDP can be an effective theranostic platform for active targeting-enhanced and image-guided cancer treatment while simultaneously reducing the systemic toxicity.

Poly-carboxylic acids functionalized chitosan nanocarriers for controlled and targeted anti-cancer drug delivery.

The present study evaluates the in-vitro cisplatin (CDDP) release from four different poly oxalates cross-linked chitosan (CS) nanocomposites. The poly oxalates were synthesized from the reaction of four different dicarboxylic acids with ethylene glycol (EG). The encapsulation of CDDP on CS cross-linked with Oxalic acid-EG, Succinic acid-EG, Citric acid-EG and tartaric acid-EG carriers were carried out by the ionic gelation technique. The poly-oxalate nanocarriers were characterized by scanning electron microscopy, atomic force microscopy, X-ray diffraction studies and zeta potential analysis. The stability of poly-oxalates was calculated by the density functional theory (DFT) using Gaussview 05. Excellent drug release kinetics and good biocompatibility of nanocomposites were observed for the in-vitro analysis. The unloaded poly oxalate nanocomposites perform to have a low inherent cytotoxicity, whereas the loaded nanocomposites were as active as free CDDP in the MCF-7 cancer cell line. The tumor growth inhibitions of CDDP-loaded nanocomposites are more or equal to that of free CDDP. Taken together, these two poly oxalate nanocomposites are established as promising drug carriers for the delivery of CDDP.

Aquated cisplatin and heparin-pluronic nanocomplexes exhibiting sustainable release of active platinum compound and NCI-H460 lung cancer cell antiproliferation

In recent decades, platinum compounds have been many contributions in medicine. Development of new drugs from the active platinum compounds as well as nanocarriers for targeted delivery and reducing side effects of the drugs has paid much attention. In the study, nanocomplexes were prepared from aquated species of cisplatin and pluronic-conjugated heparin which distributed in the range of 80–100 nm by Transmission Electron Microscopy and 134 nm by Dynamic light scattering (DLS). Formation of the complex was confirmed by FTIR and DLS. The nanocomplexes exhibited high drug-loading capacity (approximately 42.5% wt/wt at 37 °C and 37.5% wt/wt at 25 °C). In vitro, drug-loaded nanogels showed much slower release profiles of cisplatin CDDP in pH 7.4 (physiological pH) compared with pH 5.5 condition at 37 °C. Moreover, the cytotoxicity assay results also indicated that Hep-F127 was cytocompatible; meanwhile, CDDP-loaded nanocomplex was able to reduce the cytotoxic ability of free CDDP (IC50 = 5.68 ± 0.73 μg/ml), which still maintain a significantly antiproliferative activity on NCI-H460 lung cancer cell. The in vitro preliminarily obtained results indicate that the nanocomplex is a candidate for CDDP delivery which can be studied further in cancer therapy.

Cisplatin Loaded Poly(L-glutamic acid)-g-Methoxy Poly(ethylene glycol) Complex Nanoparticles for Potential Cancer Therapy: Preparation, In Vitro and In Vivo Evaluation.

A series of novel polypeptide-based graft copolymer poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol) (PLG-g-mPEG) was synthesized through a Steglich esterification reaction of PLG with mPEG. The structure of the copolymers was confirmed by nuclear magnetic resonance spectra (NMR) and gel permeation chromatography (GPC). MTT assay demonstrated that the PLG-g-mPEGs had good cell compatibility. The unreacted carboxyl groups of the PLG-g-mPEGs were used to complex cisplatin to form polymer-metal complex nanoparticles (CDDP/PLG-g-mPEG) for cancer therapy. The average hydrodynamic radius of the CDDP/PLG-g-mPEG nanoparticles was inr the range of 14-25 nm, which was beneficial for solid tumor targeting delivery. A sustained release without initial burst was achieved for the CDDP/PLG-g-mPEG nanoparticles, indicating that the CDDP-loaded nanoparticles had great potential to suppress the drug release in blood circulation before the nanoparticles had arrived at targeting tumors. The CDDP/PLG-g-mPEG nanoparticles showed a much longer blood retention profile as compared with the free CDDP. This indicated that the CDDP-loaded nanoparticles had much more opportunity to accumulate in tumor tissue by exerting the EPR effect. In vitro tests demonstrated that the CDDP/PLG-g-mPEG nanoparticles could inhibit the proliferation of HeLa, MCF-7 and A549 cancer cells. At equal dose (4 mg kg(-1)), the CDDP/PLG-g-mPEG nanoparticles showed comparable in vivo antitumor efficacy and significantly lower systemic toxicity as compared with free cis-Diaminedichloroplatinum (cisplatin, CDDP) in MCF-7 tumor bearing mice. These suggested that the CDDP/PLG-g-mPEG nanoparticle drug delivery system had a great potential to be used for cancer therapy.

Development of Alendronate-conjugated Poly (lactic-co-glycolic acid)-Dextran Nanoparticles for Active Targeting of Cisplatin in Osteosarcoma.

In this study, we developed a novel poly (lactic-co-glycolic acid)-dextran (PLD)-based nanodelivery system to enhance the anticancer potential of cisplatin (CDDP) in osteosarcoma cells. A nanosized CDDP-loaded PLGA-DX nanoparticle (PLD/CDDP) controlled the release rate of CDDP up to 48 h. In vitro cytotoxicity assay showed a superior anticancer effect for PLD/CDDP and with an appreciable cellular uptake via endocytosis-mediated pathways. PLD/CDDP exhibited significant apoptosis of MG63 cancer cells compared to that of free CDDP. Approximately ~25% of cells were in early apoptosis phase after PLD/CDDP treatment comparing to ~15% for free CDDP after 48h incubation. Similarly, PLD/CDDP exhibited ~30% of late apoptosis cells comparing to only ~8% for free drug treatment. PLD/CDDP exhibited significantly higher G2/M phase arrest in MG63 cells than compared to free CDDP with a nearly 2-fold higher arrest in case of PLD/CDDP treated group (~60%). Importantly, PLD/CDDP exhibited a most significant anti-tumor activity with maximum tumor growth inhibition. The superior inhibitory effect was further confirmed by a marked reduction in the number of CD31 stained tumor blood vessels and decrease in the Ki67 staining intensity for PLD/CDDP treated animal group. Overall, CDDP formulations could provide a promising and most effective platform in the treatment of osteosarcoma.

PH-sensitive polymeric cisplatin-ion complex with styrene-maleic acid copolymer exhibits tumor-selective drug delivery and antitumor activity as a result of the enhanced permeability and retention effect

Cisplatin (CDDP) is widely used to treat various cancers. However, its distribution to normal tissues causes serious adverse effects. For this study, we synthesized a complex of styrene-maleic acid copolymer (SMA) and CDDP (SMA–CDDP), which formed polymeric micelles, to achieve tumor-selective drug delivery based on the enhanced permeability and retention (EPR) effect. SMA–CDDP is obtained by regulating the pH of the reaction solution of SMA and CDDP. The mean SMA-CDDP particle size was 102.5nm in PBS according to electrophoretic light scattering, and the CDDP content was 20.1% (w/w). The release rate of free CDDP derivatives from the SMA–CDDP complex at physiological pH was quite slow (0.75%/day), whereas it was much faster at pH 5.5 (4.4%/day). SMA–CDDP thus had weaker in vitro toxicity at pH 7.4 but higher cytotoxicity at pH 5.5. In vivo pharmacokinetic studies showed a 5-fold higher tumor concentration of SMA–CDDP than of free CDDP. SMA–CDDP had more effective antitumor potential but lower toxicity than did free CDDP in mice after i.v. administration. Administration of parental free CDDP at 4mg/kg×3 caused a weight loss of more than 5%; SMA–CDDP at 60mg/kg (CDDP equivalent)×3 caused no significant weight change but markedly suppressed S-180 tumor growth. These findings together suggested using micelles of the SMA–CDDP complex as a cancer chemotherapeutic agent because of beneficial properties-tumor-selective accumulation and relatively rapid drug release at the acidic pH of the tumor-which resulted in superior antitumor effects and fewer side effects compared with free CDDP.

PH sensitive polymeric complex of cisplatin with hyaluronic acid exhibits tumor-targeted delivery and improved in vivo antitumor effect

Cisplatin (CDDP) is widely used anticancer drug for various solid tumors including lung cancer. However, its indiscriminate distribution causes serious adverse effects and limits its therapeutic effect. In this study, by using hyaluronic acid (HA) we synthesized a complex of CDDP (HA-CDDP), by utilizing ionic interaction between Pt2+ of CDDP with carboxyl group of HA. The mean HA-CDDP particle size was 208.5nm in PBS according to dynamic light scattering which was also confirmed by TEM, which could exert tumor-targeting property by enhanced permeability and retention (EPR) effect. The CDDP loading in this preparation was 13% (w/w), and release rate of free CDDP from the HA-CDDP complex at physiological pH (7.4) was ∼20%/day. However, in acidic pH the release was much faster, i.e., ∼95% of CDDP was released in 72h at pH 5.5. Moreover, HA-CDDP showed a 2.5-fold higher tumor accumulation than free CDDP whereas no increase of distribution was found in most normal tissues. In addition, because HA receptor CD44 is overexpressed in many tumor cells, we also observed CD44-based endocytosis of HA-CDDP in mouse lung carcinoma LCC cells. These findings together suggest that HA-CDDP may show tumor-selective cytotoxicity by taking advantage of EPR effect, weak acidic environment of tumor tissues (e.g., pH 6∼7), as well as CD44-based intracellular uptake. As expected, HA-CDDP exhibited much improved therapeutic effect than free CDDP in mouse LCC tumor model, whereas no apparent side effect was found. These findings may shed some light on the potential utility of HA for development of tumor-targeted polymeric CDDP drugs, which need further investigations.

Abstract 5517: Polymeric nanogel-based treatment regimen for enhanced efficacy and sequential administration of synergistic drug combination in pancreatic cancer

Abstract Pancreatic cancer (PC) is one of the most lethal malignancies, due to aggressive tumorigenicity, early metastasis and development of drug resistance to standard care chemotherapy. Since its approval in 1997, Gemcitabine has been the first-line treatment for advanced disease. However, there is no standard second-line therapy after Gemcitabine failure. The combination of Gemcitabine with Cisplatin (CDDP) has been explored in clinical trials for metastatic disease and our preliminary in vitro studies with the free drugs on T3M4 Simple Cells (COSMC deleted cells) showed that synergy of the combination is schedule-dependent, and Gemcitabine administration followed by CDDP showed the most potent cytotoxic activity. However, this combination proved to be only marginally effective in actual practice due to combined increased toxicity of both the agents. We have shown that encapsulation of CDDP in polymeric nanogels with cross-linked ionic cores enhanced its tumor accumulation and improved its safety profile. Additionally, sustained release profile of CDDP from nanogels allows for the administration of free Gemcitabine and CDDP loaded nanogels in a single injection while still retaining schedule-dependent synergy of the combination. Pancreatic ductal adenocarcinoma cells are known to express truncated O-glycans (Tn and STn antigens) and it is anticipated that decorating the nanogels with an antibody directed against this antigen will further enhance their uptake by tumor cells while reducing off-target accumulation. Citation Format: Kruti S. Soni, Michael A. Hollingsworth, Prakash Radhakrishnan, Tatiana K. Bronich. Polymeric nanogel-based treatment regimen for enhanced efficacy and sequential administration of synergistic drug combination in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5517. doi:10.1158/1538-7445.AM2015-5517