Anticancer Therapeutic Efficacy Research Articles

Biocompatible Drug-Antibody Conjugated Au-ZnTe Core-Shell Nanoparticles for Biosafety and Anti-Cancer Drug Delivery Applications

Biocompatible Drug-Antibody Conjugated Au-ZnTe Core-Shell Nanoparticles for Biosafety and Anti-Cancer Drug Delivery Applications There is a growing demand for the development of innovative nano-drug delivery systems that can both target and improve cancer therapies more effectively than conventional chemotherapy. Initially the biosafety of these nanoparticles must be evaluated as a compulsory component in supporting drug development research. Novel cysteine capped Au-ZnTe core-shell nanoparticles have been structurally designed using a one-pot solution based route to support surface conjugation with 5-FU and human epidermal growth factor antibody to facilitate targeted drug delivery within the domain of cancer therapeutics. The biosafety and biocompatibility of these nanoparticles was established on the cellular and whole-animal levels using in vitro and in vivo toxicity techniques. More specifically, the Au-ZnTe nanoparticles displayed no cytotoxicity effects against normal human colon, mammary epithelial and cancer cells of breast, prostate and colon origin. Moreover, under certain conditions the particles expressed cytokines in low concentrations and induced a cytotoxic response when exposed to human peripheral blood mononuclear cells. TEM and optical measurements were performed to confirm the surface conjugation of 5-FU and EGF to Au-ZnTe nanoparticles. The in vitro anti-cancer therapeutic efficacy study was performed using the MTT cytotoxicity assay on breast cancer cells. The cytotoxicity studies have shown that all components in the 5-FU-EGF-Au-ZnTe nanoparticle formulation work synergistically to attack MCF7 cancer cells displaying 19.14% increased efficacy than 5-FU at equivalent concentrations. Future work will involve pharmacokinetic and molecular modelling studies of the 5-FU-EGFAu- ZnTe nanoparticle formulation to provide further insight of its cytotoxic and drug interaction properties. This study has generated valuable new knowledge that will help scientists within the field of biotechnology, nanomedicine, biochemistry and materials chemistry, to develop and optimise strategies for more efficient therapeutic application of such materials.

RETRACTED: Enhanced antitumor efficacy of 5-fluorouracil loaded methoxy poly(ethylene glycol)–poly(lactide) nanoparticles for efficient therapy against breast cancer

In the present study, a novel nanocarrier was developed for the delivery of anticancer drug to the cancer tissues. For this purpose, 5-FU loaded methoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA) (5-FU NP) based polymeric nanoparticles was designed to increase the chemotherapeutic efficacy against breast cancers. Nanoprecipitation method was used to prepare the drug-loaded nanoparticles. The nanoparticle was evaluated in terms of DLS, TEM, in vitro release kinetics, and in vivo parameters. The average particle diameter of drug loaded NP was ∼110 nm and exhibited a sustained drug release pattern for up to 120 h. The NP exhibited a pH-response drug release pattern with accelerated release at acidic media. The in vitro cytotoxicity assay showed the enhanced cytotoxicity effect of NP formulations in comparison to free drug. The NP system showed remarkable G2/M phase cell cycle arrest with significant amount of apoptosis cells in late and early phase of flow cytometer analysis. Consistently, NP formulation greatly decreased the tumor burden of mice with no sign of adverse effect. TUNEL assay further confirmed the superior anticancer effect of NP formulations which showed a high number of apoptotic cells. The favorable results obtained from this study highlights the potential application of encapsulated 5-FU NP in the treatment of breast cancers. The remarkable anticancer therapeutic efficacy with negligible toxicity profile of 5-FU NP makes it one of the possible alternative for the successful breast cancer therapy.

Smart doxorubicin nanoparticles with high drug payload for enhanced chemotherapy against drug resistance and cancer diagnosis.

Considering the obvious advantages in efficacy and price, doxorubicin (DOX) has been widely used for a range of cancers, which is usually encapsulated in various nanocarriers for drug delivery. Although effective, in most nanocarrier-based delivery systems, the drug loading capacity of DOX is rather low; this can lead to undesired systemic toxicity and excretion concern. Herein, we report for the first time the usage of pure doxorubicin nanoparticles (DOX NPs) without addition of any carriers for enhanced chemotherapy against drug-resistance. The drug payload reaches as high as 90.47%, which largely surpassed those in previous reports. These PEG stabilized DOX NPs exhibit good biocompatibility and stability, long blood circulation time, fast release in an acidic environment and high accumulation in tumors. Compared with free DOX, DOX NPs display a dramatically enhanced anticancer therapeutic efficacy in the inhibition of cell and tumor growth. Moreover, they can also be readily incorporated with other anticancer drugs for synergistic chemotherapy to overcome the drug resistance of cancers. The fluorescence properties of DOX also endow these NPs with imaging capabilities, thus making it a multifunctional system for diagnosis and treatment. This work demonstrates great potential of DOX NPs for cancer diagnosis, therapy and overcoming drug tolerance.

Doxorubicin-loaded alginate-g-poly(N-isopropylacrylamide) micelles for cancer imaging and therapy.

Chemotherapy is a widely adopted method for the treatment of cancer. However, its use is often limited due to side effects produced by anti-cancer drugs. Therefore, various drug carriers, including polymeric micelles, have been investigated to find a method to overcome this limitation. In this study, alginate-based, self-assembled polymeric micelles were designed and prepared using alginate-g-poly(N-isopropylacrylamide) (PNIPAAm). Amino-PNIPAAm was chemically introduced to the alginate backbone via carbodiimide chemistry. The resulting polymer was dissolved in distilled water at room temperature and formed self-assembled micelles at 37 °C. Characteristics of alginate-g-PNIPAAm micelles were dependent on the molecular weight of PNIPAAm, the degree of substitution, and the polymer concentration. Doxorubicin (DOX), a model anti-cancer drug, was efficiently encapsulated in alginate-g-PNIPAAm micelles, and sustained release of DOX from the micelles was achieved at 37 °C in vitro. These micelles accumulated at the tumor site of a tumor-bearing mouse model as a result of the enhanced permeability and retention effect. Interestingly, DOX-loaded alginate-g-PNIPAAm micelles showed excellent anti-cancer therapeutic efficacy in a mouse model without any significant side effects. This approach to designing and tailoring natural polymer-based systems to fabricate nanoparticles at human body temperature may provide a useful means for cancer imaging and therapy.

Crosstalk between translesion synthesis, Fanconi anemia network, and homologous recombination repair pathways in interstrand DNA crosslink repair and development of chemoresistance.

Bifunctional alkylating and platinum based drugs are chemotherapeutic agents used to treat cancer. These agents induce DNA adducts via formation of intrastrand or interstrand (ICL) DNA crosslinks, and DNA lesions of the ICL type are particularly toxic as they block DNA replication and/or DNA transcription. However, the therapeutic efficacies of these drugs are frequently limited due to the cancer cell's enhanced ability to repair and tolerate these toxic DNA lesions. This ability to tolerate and survive the DNA damage is accomplished by a set of specialized low fidelity DNA polymerases called translesion synthesis (TLS) polymerases since high fidelity DNA polymerases are unable to replicate the damaged DNA template. TLS is a crucial initial step in ICL repair as it synthesizes DNA across the lesion thus preparing the damaged DNA template for repair by the homologous recombination (HR) pathway and Fanconi anemia (FA) network, processes critical for ICL repair. Here we review the molecular features and functional roles of TLS polymerases, discuss the collaborative interactions and cross-regulation of the TLS DNA damage tolerance pathway, the FA network and the BRCA-dependent HRR pathway, and the impact of TLS hyperactivation on development of chemoresistance. Finally, since TLS hyperactivation results from overexpression of Rad6/Rad18 ubiquitinating enzymes (fundamental components of the TLS pathway), increased PCNA ubiquitination, and/or increased recruitment of TLS polymerases, the potential benefits of selectively targeting critical components of the TLS pathway for enhancing anti-cancer therapeutic efficacy and curtailing chemotherapy-induced mutagenesis are also discussed.

Abstract LB-13: Hyaluronic acid-based CD44 targeted nanoparticle delivery of combination MDR1 siRNA/paclitaxel to overcome drug resistance in ovarian cancer

Abstract A major obstacle in the success of chemotherapy in ovarian cancer is the emergence of multidrug resistance (MDR). Overexpression of the MDR1 gene and corresponding P-glycoprotein (Pgp) efflux pumps is one of the best characterized MDR mechanisms. Although MDR1 siRNA based strategies are emerging as highly promising approaches to reverse MDR, the systemic delivery still remains a great challenge. In the present study, CD44 targeting hyaluronic acid (HA) based self-assembling nanoparticle systems were designed with MDR1 siRNA to evaluate its delivery efficiency and combination anticancer therapeutic efficacy with paclitaxel in vitro and in vivo. The results showed that HA-poly(ethyleneimine)/HA-poly(ethylene glycol) (HA-PEI/HA-PEG) nanoparticle successfully delivered MDR1 siRNA into MDR ovarian cancer cell lines, SKOV-3TR and OVCAR8TR. Western blot analysis, calcein AM retention assay, and MTT assay further demonstrated that HA-PEI/HA-PEG nanoparticles loaded with MDR1 siRNA efficiently down-regulated the expression of MDR1 and inhibited the functional activity of Pgp, and subsequently increase cell sensitivity to paclitaxel. HA-PEI/HA-PEG/MDR1 siRNA nanoparticle therapy followed by paclitaxel treatment produced a significant inhibitory effect on the drug-resistant tumor growth as compared with control groups in MDR ovarian cancer xenograft mouse models. These results indicated CD44-targeted HA-PEI/HA-PEG nanoparticle platform is an effective siRNA delivery system for potential siRNA-based anticancer therapeutics in ovarian cancer. Citation Format: Xiaoqian Yang, Arun lyer, Francis hornicek, Mansoor Amiji, Zhenfeng Duan. Hyaluronic acid-based CD44 targeted nanoparticle delivery of combination MDR1 siRNA/paclitaxel to overcome drug resistance in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-13. doi:10.1158/1538-7445.AM2014-LB-13

Anticancer drug-incorporated layered double hydroxide nanohybrids and their enhanced anticancer therapeutic efficacy in combination cancer treatment.

Objective. Layered double hydroxide (LDH) nanoparticles have been studied as cellular delivery carriers for anionic anticancer agents. As MTX and 5-FU are clinically utilized anticancer drugs in combination therapy, we aimed to enhance the therapeutic performance with the help of LDH nanoparticles. Method. Anticancer drugs, MTX and 5-FU, and their combination, were incorporated into LDH by reconstruction method. Simply, LDHs were thermally pretreated at 400°C, and then reacted with drug solution to simultaneously form drug-incorporated LDH. Thus prepared MTX/LDH (ML), 5-FU/LDH (FL), and (MTX + 5-FU)/LDH (MFL) nanohybrids were characterized by X-ray diffractometer, scanning electron microscopy, infrared spectroscopy, thermal analysis, zeta potential measurement, dynamic light scattering, and so forth. The nanohybrids were administrated to the human cervical adenocarcinoma, HeLa cells, in concentration-dependent manner, comparing with drug itself to verify the enhanced therapeutic efficacy. Conclusion. All the nanohybrids successfully accommodated intended drug molecules in their house-of-card-like structures during reconstruction reaction. It was found that the anticancer efficacy of MFL nanohybrid was higher than other nanohybrids, free drugs, or their mixtures, which means the multidrug-incorporated LDH nanohybrids could be potential drug delivery carriers for efficient cancer treatment via combination therapy.

PH-responsive and charge shielded cationic micelle of poly(l-histidine)-block-short branched PEI for acidic cancer treatment

To address cancer cell heterogeneity while endowing tumor specificity, the approach of charge shielding/deshielding was tested in vitro and in vivo with a paclitaxel loaded cationic micelle from a block copolymer of poly(l-histidine) (3.7kDa) and short branched polyethyleneimine (1.8kDa). The cationic micelle surface was shielded by electrostatically complexing with a negatively charged mPEG (2kDa)-block-polysulfadimethoxine (4kDa) (mPEG-b-PSDM) at pH7.4. Unshielded micelle at pH7.4 and deshielded micelle at tumor extracellular pH were readily taken up by two wild types of human cancer cell lines, MCF-7 breast adenocarcinoma and SKOV-3 ovarian carcinoma, while the uptake of the shielded micelle at pH7.4 was minimal. The preliminary in vivo results from a mouse model xenografted with MCF-7 showed significant anticancer therapeutic efficacy and deep penetration of the micelle into tumor tissues after deshielding, supporting the unique pH-responsive mechanism to treat acidic cancer.

Deep Penetration of Nanoparticulate Drug Delivery Systems into Tumors: Challenges and Solutions

In recent decades, nanoparticulate drug delivery systems have attracted extensive attention in cancer therapy for such appealing properties as small particle size, huge surface area, narrow size distribution and prolonged circulation time. Although several nanomedicines have successfully reached the clinical, evidences have proved that therapeutic efficacy isn't improved significantly, except for better toleration and less side effects. Given that the physiological abnormalities in tumors, multiple biobarriers need to be overcome before nanomedicines are delivered to the target site. Passive targeting nanoparticles ensure nanomedicines' extensive extravasation from tumor vessels via enhanced permeation and retention effect, but the diffusion distance is limited to 2-3 cell layer thicknesses. Active targeting nanoparticles tend to bind the peripheral cells of the tumor mass, hindering nanoparticles further penetration into the tumor core region. Therefore, how to improve the deep penetration of nanomedicines into tumors is a formidable task for achieving the desired anticancer therapeutic efficacy. This review demonstrates the penetration obstacles existing in tumor region for nanoparticles, summarizes the important properties of nanomedicines affecting tumor deep penetration and highlights the solutions to improve tumor deep penetration of nanoparticles.

Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers.

For almost four decades, my work has focused on one challenge: improving the delivery and efficacy of anticancer therapeutics. Working on the hypothesis that the abnormal tumor microenvironment-characterized by hypoxia and high interstitial fluid pressure--fuels tumor progression and treatment resistance, we developed an array of sophisticated imaging technologies and animal models as well as mathematic models to unravel the complex biology of tumors. Using these tools, we demonstrated that the blood and lymphatic vasculature, fibroblasts, immune cells, and extracellular matrix associated with tumors are abnormal, which together create a hostile tumor microenvironment. We next hypothesized that agents that induce normalization of the microenvironment can improve treatment outcome. Indeed, we demonstrated that judicious use of antiangiogenic agents--originally designed to starve tumors--could transiently normalize tumor vasculature, alleviate hypoxia, increase delivery of drugs and antitumor immune cells, and improve the outcome of various therapies. Our trials of antiangiogenics in patients with newly diagnosed and recurrent glioblastoma supported this concept. They revealed that patients whose tumor blood perfusion increased in response to cediranib survived 6 to 9 months longer than those whose blood perfusion did not increase. The normalization hypothesis also opened doors to treating various nonmalignant diseases characterized by abnormal vasculature, such as neurofibromatosis type 2. More recently, we discovered that antifibrosis drugs capable of normalizing the tumor microenvironment can improve the delivery and efficacy of nano- and molecular medicines. Our current efforts are directed at identifying predictive biomarkers and more-effective strategies to normalize the tumor microenvironment for enhancing anticancer therapies.

Preparation, characterization and anticancer therapeutic efficacy of cisplatin-loaded niosomes

This study developed a carrier for anticancer drug, cisplatin. Cisplatin-loaded niosomes (CP-NMs) were prepared under optimized conditions with Span 40 and cholesterol as the excipients, and then lyophilized and characterized. Their anticancer efficacy was tested in rabbits bearing VX2 sarcoma. The obtained spherical-looking vesicles showed a diameter of 7.73 ± 1.49 µm with a zeta-potential of 0 mV. The entrapment efficiency was 76.93 ± 2.67%, and drug loading 2.96 ± 0.10%. In vitro release tests gave a t50% of 8.36 h. The rabbits locally injected with the CP-NMs gave significantly superior results of inhibition of tumour growth, much lower mortality and improved results of body weight change and inhibition of tumour metastasis to inguinal lymph nodes and liver compared to those treated in the same way with the drug solution. The inspiring anticancer results indicated that the CP-NMs might be developed as an effective anticancer preparation with low toxicity.

Concurrent blockade of NF-κB and Akt pathways potentiates cisplatin’s antitumor activity in vivo

Nuclear factor-κB (NF-κB) and Akt are two major cell-survival pathways that are often constitutively activated in cancer cells. It has been established that these two pathways contribute substantially toward the chemoresistance of cancer cells. Our previous study has demonstrated that NF-κB and Akt cooperatively blunt cytotoxicity induced by cisplatin or etopside in different types of cancer cells in vitro, indicating that the concurrent blocking of these pathways may effectively improve the anticancer efficacy of anticancer therapeutics. In this study, we further investigated the effect of concurrent blockade of NF-κB and Akt on the anticancer activity of cisplatin in vivo in a xenograft tumor model. The NF-κB and Akt pathways in the A549 lung cancer cells were blocked individually or concurrently by the stable transfection of plasmids expressing short hairpin RNAs that target Akt1 and IκB kinase β. The resultant cells with concurrent NF-κB and Akt blockade were significantly more sensitive to cisplatin-induced cell death in vitro. Consistently, tumors derived from cells with the concurrent blockade of NF-κB and Akt were much more sensitive to cisplatin compared with those derived from cells with individual blockage of NF-κB or Akt in a nude mouse xenograft tumor model. Apoptosis was significantly enhanced in the double pathway-suppressed and cisplatin-treated tumors. These results show for the first time that the concurrent blockage of the NF-κB and Akt pathways cooperatively potentiates the antitumor activity of cisplatin in vivo, indicating that this strategy may be potentially useful for clinical anticancer therapy.

Comparison of the effects of Mylabris and Acanthopanax senticosus on promising cancer marker polyamines in plasma of a Hepatoma‐22 mouse model using HPLC‐ESI‐MS

A simple and sensitive method for the simultaneous determination of plasma concentrations of five polyamines in normal and Hepatoma-22 mice, and mice treated with Mylabris and Acanthopanax senticosus was developed by HPLC-ESI-MS. Male Kunming mice were divided into nine groups, a control group (inoculation without treatment), a positive group (Cyclophosphamide), treatment groups [Mylabris (4, 8, 16 mg/kg), Acanthopanax senticosus (6, 12, 24 g/kg)] and a normal group (without inoculation). Twenty-four hours after the last administration, plasma samples were collected. The derived polyamines were separated on a C(18) column by a gradient elution using methanol-water with excellent linearity within the range from 2.5 to 1000 ng/mL. Polyamines were confirmed as useful biochemical markers of hepatoma. The differences in anti-cancer therapeutic efficacy between Mylabris and Acanthopanax senticosus might contribute to the variability of polyamine levels in vivo. This HPLC-ESI-MS method was successfully applied to investigate the relationship between polyamines and cancer in mice and might be a useful method to test the activity of potential anti-tumor drugs.

Colon cancer stem cells – From basic to clinical application

Based on cancer stem cell (CSC) concept of carcinogenesis, tumors represent complex heterogeneous organ-like systems with a hierarchical cellular organization, and only minority phenotypic subpopulations with stem-like properties possess a dual ability to self-renew indefinitely and produce all the heterogeneous cell phenotypes comprising the bulk tumor cells. Large experimental and clinical data indicate that conventional anti-cancer therapies cannot eradicate CSCs, and moreover, they usually increase their number leading to cancer recurrence and further drug resistance. In this review, several current controversies in the CSC field and recent studies, which help to shed light on their origin, are discussed. The emerging necessity for the development of complex, multimodal CSC-targeted treatment strategies, which combine conventional therapeutics with promising pathway-specific modulators, and natural compounds, which can improve the efficacy of conventional anti-cancer therapeutics and decrease their undesirable side effects is presented. Also, novel requirements and criteria necessary for evaluation of the CSC-targeted drug efficacy and relevant experimental models are discussed.

Tumor-binding prodrug micelles of polymer–drug conjugates for anticancer therapy in HeLa cells

An interesting phytosphingosine (PHS), a natural sphingolipid metabolite comprising ceramides, is believed to play a vital role in strong anticancer therapeutic efficacy for various types of cancer cells, which is based on a programmed cellular death mechanism, so called apoptosis. However, extremely low water-solubility has been an obstacle to its usage as an anticancer drug via the systemic administration route. To utilize the benefits of PHS, we developed tumor-targeting polymer–drug conjugates wherein hydrophobic PHS was connected to the folate-grafted hydrophilic and biocompatible polymer through pH-sensitive linkages. The polymer–drug conjugates formed nano-sized (10–20 nm) spherical micelles spontaneously in aqueous media and they were found to have high drug contents (10.3 wt%). We present a systematic study of in vitro anticancer therapy in HeLa cells treated by tumor-targeting micelles in terms of anti-proliferation. The anticancer effect was analyzed by apoptotic cell death as well as the preferential distribution of loaded drug in the cancer cells. The synergistic effect by loading the commercial drug of doxorubicin was also studied.

Akt/mTOR Counteract the Antitumor Activities of Cixutumumab, an Anti-Insulin–like Growth Factor I Receptor Monoclonal Antibody

Recent reports have shown limited anticancer therapeutic efficacy of insulin-like growth factor receptor (IGF-1R)-targeted monoclonal antibodies (mAb), but the resistance mechanisms have not been completely identified. Because cooperation between epidermal growth factor receptor (EGFR) and IGF-IR could cause resistance to inhibitors of individual receptor tyrosine kinases, we investigated the involvement of EGFR signaling in resistance to IGF-1R mAb and the underlying mechanisms of action. Most head and neck squamous cell carcinoma (HNSCC) tissues had coexpression of total and phosphorylated IGF-1R and EGFR at high levels compared with paired adjacent normal tissues. Treatment with cixutumumab (IMC-A12), a fully humanized IgG1 mAb, induced activation of Akt and mTOR, resulting in de novo synthesis of EGFR, Akt1, and survivin proteins and activation of the EGFR pathway in cixutumumab-resistant HNSCC and non-small cell lung cancer (NSCLC) cells. Targeting mTOR and EGFR pathways by treatment with rapamycin and cetuximab (an anti-EGFR mAb), respectively, prevented cixutumumab-induced expression of EGFR, Akt, and survivin and induced synergistic antitumor effects in vitro and in vivo. These data show that resistance to IGF-1R inhibition by mAbs is associated with Akt/mTOR-directed enhanced synthesis of EGFR, Akt1, and survivin. Our findings suggest that Akt/mTOR might be effective targets to overcome the resistance to IGF-1R mAbs in HNSCC and NSCLC.

Highlights of This Issue

Insulin-like growth factor receptor (IGF-1R)-targeted monoclonal antibodies (mAb) have shown limited anticancer therapeutic efficacy. In this study, Shin and colleagues investigated the mechanisms of resistance to a fully humanized anti-IGF-1R mAb cixutumumab in head and neck squamous cell carcinoma (HNSCC). They found that resistance to IGF-1R inhibition by cixutumumab was associated with Akt/mammalian target of rapamycin (mTOR)-mediated de novo protein synthesis of EGFR, Akt1, and survivin and activation of the EGFR pathway, and cotargeting IGF-1R/mTOR had synergistic antitumor effects in vitro and in vivo. These results show potential clinical use of cotargeting IGF-1R and Akt/mTOR in patients with HNSCC.Cellular bioenergetics is an emerging therapeutic target in cancer. Despite the Warburg effect playing a critical role in providing bioenergetics to tumor cells, inhibition of glycolysis alone showed limited efficacy in clinical trials. Cheong and colleagues show that activation of AMPK as a consequence of decreased glycolysis increases transcription of genes in cellular respiration, thereby bypassing the effect of decreased glycolysis. Dual inhibition of both glycolysis with glycolysis inhibitor 2-deoxyglucose and oxidative phosphorylation with metformin leads to marked decrease in ATP and cell death, which is sufficient to suppress tumor growth in vivo. This combination could be readily and rapidly translated to the clinic.The JAK/STAT pathway has been linked to multiple cancers including glioblastoma (GBM). McFarland and colleagues tested the therapeutic potential of AZD1480, a newly developed JAK1/2 inhibitor in GBM. Patient-derived human GBM xenografts serially maintained in the flanks of nude mice were profiled and chosen for the study based on high JAK/STAT-3 activation. AZD1480 treatment inhibited the growth of the xenograft flank tumors and prolonged survival in an orthotopic model, which was attributed to decreased STAT-3 signaling. AZD1480 may potentially be an effective antitumor agent when combined with current therapies available for GBM.The phosphoinositide-3 kinase (PI3K)/Akt signaling pathway is fundamental to numerous cellular processes. Abnormal activation of the pathway has been implicated in many cancers and therefore represents an attractive target for therapeutic intervention. GDC-0980 is a potent and selective inhibitor of Class I PI3K and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. Wallin and colleagues report that GDC-0980 potently inhibits xenograft growth of various malignancies and the effects on tumor growth correlate with changes in pharmacodynamic biomarkers. Thus, GDC-0980 is a promising therapeutic candidate for clinical cancer development.

Nuclear Targeting Dynamics of Gold Nanoclusters for Enhanced Therapy of HER2+ Breast Cancer

Recent advances in fluorescent metal nanoclusters have spurred tremendous interest in nanomedicine due to the ease of fabrication, excellent biocompatibility, and, more importantly, excellent wavelength-dependent tunability. Herein, we report our findings on fluorescent BSA-protected gold nanoclusters (AuNCs), ∼2 nm in size conjugated with Herceptin (AuNCs-Her), for specific targeting and nuclear localization in ErbB2 over-expressing breast cancer cells and tumor tissue as a novel fluorescent agent for simultaneous imaging and cancer therapy. More interestingly, we found that AuNCs-Her could escape the endolysosomal pathway and enter the nucleus of cancer cells to enhance the therapeutic efficacy of Herceptin. We elucidate the diffusion characteristics (diffusion time and number of diffusers) and concentration of the fluorescing clusters in the nucleus of live cells. Our findings also suggest that the nuclear localization effect of AuNCs-Her enhances the anticancer therapeutic efficacy of Herceptin as evidenced by the induction of DNA damage. This study not only discusses a new nanomaterial platform for nuclear delivery of drugs but also provides important insights on nuclear targeting for enhanced therapy.

Characterization of PEGylated nanoliposomes co-remotely loaded with topotecan and vincristine: relating structure and pharmacokinetics to therapeutic efficacy

Recently, developing drug delivery systems exhibiting controlled drug release at the tumor sites emerged as an attractive option for enhancing anticancer therapeutic efficacy. It seems, however, unlikely that single agent therapies will prove effective enough against the myriad cells present within the malignancy. Therefore, next generation nanotherapeutics must not only find their way to the solid tumor but also must effectively destroy the diverse populations of cells promoting tumor growth. Nanoliposomes offer an important advantage in the delivery of a combination of drugs acting synergistically in cancer treatment. They allow controlling the pharmacokinetics and biodistribution of the drugs by uniform time and spatial co-delivery of the agents. However, successful translation of such complex formulations into the clinic relies on understanding critical physicochemical characteristics. These include: liposomes’ membrane phase and dynamics, size distribution, state of encapsulated drug, internal environment of liposome, state of grafted polyethylene glycol at the liposome surface, and in-vivo drug release rate. They determine the pharmacokinetics of the formulation and the bioavailability of the drugs.We encapsulated the combination of vincristine (VCR) and topotecan (TPT) in the same nanoliposome (LipoViTo). Our in-vitro and in-vivo characterization of LipoViTo provides an explanation for the good therapeutic efficacy that was previously reported by us. Moreover, we have described how to study these critical features for a two-drug in one nanoliposome formulation. This characterization is an important step for a rational clinical development and for how to ensure liposome product quality of LipoViTo and other liposomal formulations alike.

Promiscuous survivin peptide induces robust CD4+ T‐cell responses in the majority of vaccinated cancer patients

CD4(+) T cells have been shown to be crucial for the induction and maintenance of cytotoxic T cell responses and to be also capable of mediating direct tumor rejection. Therefore, the anticancer therapeutic efficacy of peptide-based vaccines may be improved by addition of HLA class II epitopes to stimulate T helper cells. Survivin is an apoptosis inhibiting protein frequently overexpressed in tumors. Here we describe the first immunological evaluation of a survivin-derived CD4(+) T cell epitope in a multipeptide immunotherapy trial for prostate carcinoma patients. The survivin peptide is promiscuously presented by several human HLA-DRB1 molecules and, most importantly, is naturally processed by dendritic cells. In vaccinated patients, it was able to induce frequent, robust and multifunctional CD4(+) T cell responses, as monitored by IFN-γ ELISPOT and intracellular cytokine staining. Thus, this HLA-DR restricted epitope is broadly immunogenic and should be valuable for stimulating T helper cells in patients suffering from a wide range of tumors.