Antiproliferative effect of immunoliposomes containing 5-fluorodeoxyuridine-dipalmitate on colon cancer cells.

We have investigated the antiproliferative action towards CC531 colon adenocarcinoma cells of target cell-specific immunoliposomes containing the amphiphilic dipalmitoyl derivative of 5-fluorodeoxyuridine (FUdR-dP). FUdR-dP incorporated in immunoliposomes caused a 13-fold stronger inhibition of CC531 cell growth in vitro, during a 72-h treatment, than FUdR-dP in liposomes without antibody, demonstrating that the prodrug is efficiently hydrolysed to yield the active drug, FUdR, intracellularly. The intracellular release of active FUdR was confirmed by determining the fate of 3H-labelled immunoliposomal FUdR-dP. Treatments shorter than 72 h with FUdR-dP in immunoliposomes resulted in anti-tumour activities comparable to, or even higher than, that of free FUdR. The shorter treatments reflect more closely the in vivo situation and illustrate the potential advantage of the use of immunoliposomes over non-targeted liposomal FUdR-dP or free FUdR. Association of tumour cell-specific immunoliposomes with CC531 cells was up to tenfold higher than that of liposomes without antibody or with irrelevant IgG coupled, demonstrating a specific interaction between liposomes and target cells which causes an efficient intracellular delivery of the drug. Since biochemical evidence indicates a lack of internalization or degradation of the liposomes as such, we postulate that entry of the drug most likely involves the direct transfer of the prodrug from the immunoliposome to the cell membrane during its antigen-specific interaction with the cells, followed by hydrolysis of FUdR-dP leading to relatively high intracellular FUdR-levels. In conclusion, we describe a targeted liposomal formulation for the anticancer drug FUdR, which is able to deliver the active drug to colon carcinoma cells with high efficiency, without the need for the cells to internalize the liposomes as such.     

Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer

Even with current promising antitumor antibodies, their antitumor effects on stroma‐rich solid cancers have been insufficient. We used mild hyperthermia with the intent of improving drug delivery by breaking the stromal barrier. Here, we provide preclinical evidence of cetuximab + mild hyperthermia therapy. We used four in vivo pancreatic cancer xenograft mouse models with different stroma amounts (scarce, MIAPaCa‐2; moderate, BxPC‐3; and abundant, Capan‐1 and Ope‐xeno). Cetuximab (1 mg/kg) was given systemically, and the mouse leg tumors were concurrently heated using a water bath method for 30 min at three different temperatures, 25°C (control), 37°C (intra‐abdominal organ level), or 41°C (mild hyperthermia) (n = 4, each group). The evaluated variables were the antitumor effects, represented by tumor volume, and in vivo cetuximab accumulation, indirectly quantified by the immunohistochemical fluorescence intensity value/cell using antibodies against human IgG Fc. At 25°C, the antitumor effects were sufficient, with a cetuximab accumulation value (florescence intensity/cell) of 1632, in the MIAPaCa‐2 model, moderate (1063) in the BxPC‐3 model, and negative in the Capan‐1 and Ope‐xeno models (760, 461). By applying 37°C or 41°C heat, antitumor effects were enhanced shown in decreased tumor volumes. These enhanced effects were accompanied by boosted cetuximab accumulation, which increased by 2.8‐fold (2980, 3015) in the BxPC‐3 model, 2.5‐ or 4.8‐fold (1881, 3615) in the Capan‐1 model, and 3.2‐ or 4.2‐fold (1469, 1922) in the Ope‐xeno model, respectively. Cetuximab was effective in treating even stroma‐rich and k‐ras mutant pancreatic cancer mouse models when the drug delivery was improved by combination with mild hyperthermia.     

Multistage delivery of chemotherapeutic nanoparticles for breast cancer treatment

Adequate drug delivery to tumors is hindered by barriers such as degradation and non-specific distribution. Nested incorporation of drug-containing nanoparticles within mesoporous silicon particles (MSVs), carriers rationally designed to enhance tumor transport, was hypothesized to result in pronounced and sustained antitumor efficacy. Paclitaxel (PTX)-containing poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) polymer micelles were favorably loaded within MSVs, after which drug release was significantly delayed. Antitumor efficacy analyses in mice bearing MDA-MB-468 breast tumors demonstrated significant tumor growth suppression following a single administration. Results highlight effective chemotherapeutic shuttling and site-specific controlled release afforded by MSVs, potentially translating towards improvements in patient outcomes and morbidity.     

Tumor-associated antigens in bilateral breast cancer

The purpose of our present study is to determine whether monoclonal antibodies can define an antigenic phenotype which expresses itself in a concordant fashion in synchronous bilateral breast cancer. The monoclonal antibodies DF.3 and B72.3 were reacted (ABC immunoperoxidase) with formalin-fixed, paraffin-embedded sections of bilateral synchronous breast cancers from 19 patients. MAb DF.3 demonstrated a P less than .01 correlation of right-sided vs left-sided reactivity. This suggested that MAb DF.3 could be used as a biologic marker for synchronous bilateral breast cancer. We hypothesized that the majority of clinically asynchronous breast cancers are really biologically synchronous. We used the immunoperoxidase technique in a similar fashion on bilateral metachronous tumors in 17 patients. DF.3 antigen expression correlated (right to left side) at P less than .01 value. This data, supported by previous information, suggests that the term "metachronous" breast cancer is a clinically arbitrary definition but that biologically most "metachronous" cancers may well be synchronous.     

pH-responsive mesoporous silica nanoparticles employed in controlled drug delivery systems for cancer treatment

In the fight against cancer, controlled drug delivery systems have emerged to enhance the therapeutic efficacy and safety of anti-cancer drugs. Among these systems, mesoporous silica nanoparticles （MSNs） with a functional surface possess obvious advantages and were thus rapidly developed for cancer treatment. Many stimuli-responsive materials, such as nanopartides, polymers, and inorganic materials, have been applied as caps and gatekeepers to control drug release from MSNs. This review presents an overview of the recent progress in the production of pH-responsive MSNs based on the pH gradient between normal tissues and the tumor microenvironment. Four main categories of gatekeepers can respond to acidic conditions. These categories will be described in detail.     

Efficacy of immunoliposomes on cancer models in a cell-surface-antigen-density-dependent manner

We have recently established a cancer-reactive human monoclonal antibody, GAH, with a positive ratio of over 90% against stomach cancer. GAH was formulated as polyethyleneglycol (PEG)-modified immunoliposomal doxorubicin (DXR) (ILD) and its efficacy was examined against gastrointestinal human cancers. In in vitro studies, a comparison of ILD with PEG-modified liposomal DXR (LD) demonstrated that ILD had dose-dependent cytotoxicity for GAH-reactive B37 cancer cells, but not LD. In concordance with this result, microscopic observations showed that ILD was bound to and GAH-dependently internalised by B37 cells. In in vivo studies, ILD exhibited significantly greater antitumour activity on cancer xenograft models than LD or free DXR. The relation between efficacy and antigen density was examined on 10 xenograft models bearing cancer cells with varying GAH reactivity. Immunoliposomal doxorubicin therapeutic activity correlated with the antigen density, with a minimum number being required. Also, ILD revealed strong antitumour activity on cancers with low sensitivity to DXR or LD, suggesting that ILD overcame the DXR resistance of antigen-positive cancer cells. Thus, these results show that GAH endows liposomes with targeting activity, resulting in strong efficacy against gastrointestinal cancers.     

Nanoparticle drug delivery to target breast cancer brain metastasis: Current and future trends

Breast cancer brain metastasis (BCBM) is rapidly becoming an impediment to continuing survival gains seen in breast cancer patients. Drug delivery across the blood-brain barrier is the main issue hindering systemic therapy against BCBM. This review details recent advances in nanoparticle (NP) drug delivery systems to target BCBM. Their primary benefits are: enhanced circulating and intra-BCBM drug biodistribution, BCBM targeting through NP functionalization, opportunities for gene manipulation and their theragnostic applications. Multiple NPs have been synthesized to deliver therapeutic HER2 blockade, which is particularly important given HER2-positive breast cancer's tendency to form BCBM. Finally, we review the clinical context in which NP-based therapeutics have been investigated in BCBM patients. While a breakthrough in improving patient outcomes remain awaited, these clinical trials represent positive steps in the changing attitude towards BCBM as a treatable illness. Although multiple challenges remain in the clinical translation of BCBM-directed NP therapies, ongoing research in the field offers promising avenues for novel targeting of this devastating disease.     

Specific binding of TES-23 antibody to tumour vascular endothelium in mice, rats and human cancer tissue: a novel drug carrier for cancer targeting therapy

The tissue distribution of anti-tumour vascular endothelium monoclonal antibody (TES-23) produced by immunizing with plasma membrane vesicles from isolated rat tumour-derived endothelial cells (TECs) was assessed in various tumour-bearing animals. Radiolabelled TES-23 dramatically accumulated in KMT-17 fibrosarcoma, the source of isolated TECs after intravenous injection. In Meth-A fibrosarcoma, Colon-26 adenocarcinoma in BALB/c mice and HT-1080 human tumour tissue in nude mice, radioactivities of 125I-labelled TES-23 were also up to 50 times higher than those of control antibody with little distribution to normal tissues. The selective recognition of TES-23 to TECs was competitively blocked by preadministration of unlabelled TES-23 in vivo. Furthermore, immunostaining of human tissue sections showed specific binding of TES-23 on endothelium in oesophagus cancers. These results indicate that tumour vascular endothelial cells express common antigen in different tumour types of various animal species. In order to clarify the efficacy of TES-23 as a drug carrier, an immunoconjugate, composed of TES-23 and neocarzinostatin, was tested for its anti-tumour effect in rats bearing KMT-17 fibrosarcomas. The immunoconjugate (TES-23-NCS) caused marked regression of the tumour, accompanied by haemorrhagic necrosis. Thus, from a clinical view, TES-23 would be a novel drug carrier because of its high specificity to tumour vascular endothelium and its application to many types of cancer.     

Mathematical spatio-temporal model of drug delivery from low temperature sensitive liposomes during radiofrequency tumour ablation

Purpose: Studies have demonstrated a synergistic effect between hyperthermia and chemotherapy, and clinical trials in image-guided drug delivery combine high-temperature thermal therapy (ablation) with chemotherapy agents released in the heating zone via low temperature sensitive liposomes (LTSL). The complex interplay between heat-based cancer treatments such as thermal ablation and chemotherapy may require computational models to identify the relationship between heat exposure and pharmacokinetics in order to optimise drug delivery.

Materials and methods: Spatio-temporal data on tissue temperature and perfusion from heat-transfer models of radiofrequency ablation were used as input data. A spatio-temporal multi-compartmental pharmacokinetic model was built to describe the release of doxorubicin (DOX) from LTSL into the tumour plasma space, and subsequent transport into the extracellular space, and the cells. Systemic plasma and tissue compartments were also included. We compared standard chemotherapy (free-DOX) to LTSL-DOX administered as bolus at a dose of 0.7 mg/kg body weight.

Results: Modelling LTSL-DOX treatment resulted in tumour tissue drug concentration of ～9.3 µg/g with highest values within 1 cm outside the ablation zone boundary. Free-DOX treatment produced comparably uniform tissue drug concentrations of ～3.0 µg/g. Administration of free-DOX resulted in a considerably higher peak level of drug concentration in the systemic plasma compartment (16.1 µg/g) compared to LTSL-DOX (4.4 µg/g). These results correlate well with a prior in vivo study.

Conclusions: Combination of LTSL-DOX with thermal ablation allows localised drug delivery with higher tumour tissue concentrations than conventional chemotherapy. Our model may facilitate drug delivery optimisation via investigation of the interplays among liposome properties, tumour perfusion, and heating regimen.     

Enhanced delivery of synthetic oligonucleotides to human leukaemic cells by liposomes and immunoliposomes

The ability of pH-sensitive liposomes and immunoliposomes to deliver synthetic antisense oligonucleotides (oligos) into human myeloid and lymphoid leukaemia cells was examined. The cellular uptake of an 18mer anti-myb oligonucleotide encapsulated in liposomes was from three- to five-fold higher than that of ³²P-oligos alone. In addition, anti-CD32 or anti-CD2 immunoliposomes improved the delivery of oligos to leukaemic cells carrying the appropriate receptor for the specific antibody-linked immunoliposome. The uptake of oligos was twice that of the liposome or non-specific immunoliposome encapsulated oligos. These findings support the use of liposomes or immunoliposomes to deliver antisense oligos into human leukaemic cells.     

Relationship between physico-chemical properties of magnetic fluids and their heating capacity

Abstract

The final goal in magnetic hyperthermia research is to use nanoparticles in the form of a colloidal suspension injected into human beings for a therapeutic application. Therefore the challenge is not only to develop magnetic nanoparticles with good heating capacities, but also with good colloidal properties, long blood circulation time and with grafted ligands able to facilitate their specific internalisation in tumour cells. Significant advances have been achieved optimising the properties of the magnetic nanoparticles, showing extremely large specific absorption rate values that will contribute to a reduction in the concentration of the magnetic fluid that needs to be administered. In this review we show the effect of different characteristics of the magnetic particles, such as size, size distribution and shape, and the colloidal properties of their aqueous suspensions, such as hydrodynamic size and surface modification, on the heating capacity of the magnetic colloids.     

纳米靶向给药系统与口腔癌治疗

口腔癌是头颈部较常见的恶性肿瘤之一,被动靶向是口腔癌最初的靶向治疗,靶向性差.为了更好地实现对口腔癌靶向治疗,近年来学者们转向于研究主动靶向纳米给药系统,即将靶分子连接在纳米粒表面,使其与肿瘤细胞表面特异性表达或者过度表达的某种受体结合而实现靶向,该靶向系统可将抗肿瘤药物定向输送于病变部位,达到降低不良反应、增加疗效的目的.靶向性化疗已成为口腔癌治疗的趋势.     

Future developments in the selectivity of anticancer agents: Drug delivery and molecular target strategies

In the past, our limited understanding of the processes involved in the initiation and growth of cancer hindered our ability to effectively treat most human malignancies and therapies were often associated with significant toxic side effects as well as re-emergence of disease. The development of drug delivery systems such as liposomes has improved the specificity of various conventional anticancer agents by enhancing drug accumulation in tumors while often decreasing exposure to susceptible healthy tissues. More recently, the identification of a wide range of genes and corresponding protein products that are altered in various human cancers has revealed new molecular targets for cancer therapy that may provide improved selectivity for tumor cells over traditional cytotoxic agents. This review discusses how advances in the sophistication of liposomal delivery systems may open new opportunities for combining novel molecular targeting strategies with pharmacological targeting via liposomes to optimize the therapy of many human malignancies.     

New frontiers in oncology: biosimilar monoclonal antibodies for the treatment of breast cancer

Trastuzumab is a highly successful monoclonal antibody (mAb) that has been used primarily for the treatment of HER2-positive breast cancer. Because of its success and its impending patent expiry in Europe in 2014, a number of copy versions of trastuzumab have been developed and are currently undergoing a comparability exercise for marketing authorization. Although biosimilar products have been approved in Europe since 2006, including two biosimilar mAbs of infliximab approved in 2013, the use of mAbs such as trastuzumab in the cancer setting has raised a number of new concerns. The requirements for the approval of biosimilar mAbs published by the EMA will be discussed and examined in the context of trastuzumab biosimilars to highlight potential controversies.     

Tumour tissue transport after intraperitoneal anticancer drug delivery

Abstract

Intraperitoneal (IP) drug delivery, either as an intraoperative chemoperfusion or as an adjuvant, repeated instillation, is an established treatment modality in patients with peritoneal carcinomatosis. The efficacy of IP drugs depends on its ability to penetrate the tumour stroma in order to reach their (sub)cellular target. It is known, that drug penetration after IP delivery is limited to a few millimetres. Here, we review the basic tissue transport mechanisms after IP delivery and discuss the biophysical barriers and obstacles that limit penetration distance. In addition, we review the physical and pharmaceutical interventions that have been studied in order to improve delivery of small molecular and macromolecular drugs after IP instillation. These interventions could inform the design of future clinical trials aiming at an improved efficacy of IP-based drug delivery in carcinomatosis patients.     

表皮生长因子受体与肿瘤治疗

表皮生长因子受体(EGFR)是一个家族,在不同肿瘤中均有高表达.EGFR活化会增加肿瘤细胞的增殖、侵袭、转移,因此EGFR的抑制剂成为重要的治疗肿瘤新药,EGFR成为治疗肿瘤的分子靶区.EGFR抑制剂包括小分子化合物和单克隆抗休两大类,临床试验表明在肿瘤治疗上两者都有很大价值.     

Use of ultrasound in drug delivery systems: emphasis on experimental methodology and mechanisms

Recent studies have shown that ultrasound energy could be applied for targeting or controlling drug release. This new concept of therapeutic ultrasound combined with drugs has induced a great amount of interest in various medical fields. In this paper, several experimental systems are cited in which ultrasound is being utilized to evaluate new application of this modality. The mechanisms of ultrasound-mediated drug delivery are discussed in addition to the review of current advances in the use of ultrasound in systems involving research in cancer therapy, gene therapy, microbubbles and other drug delivery in vitro and in vivo experiments.     

大肠癌同时性肝转移癌应用植入式药泵25例治疗观察

目的探讨大肠癌同时性肝转移癌不能切除，术中同时应用植入式药泵化疗栓塞的作用。方法在切除原发病灶的同时对不能切除的肝转移癌在术中同时置入肝动脉植入式药泵并给予化疗栓塞。使用药物FUDR+DDP+EADM+碘化油，观察存活率。结果5年存活率8%、3年存活率56%、2年存活率24%、1年存活率12%。结论对于大肠癌同时性肝转移癌不能切除者采用植入式药泵化疗栓塞，具有明显提高存活率。使用植入式药泵操作简单、疗效显著、并发症少，具有较高的应用价值。     

Use of bacterial magnetosomes in the magnetic hyperthermia treatment of tumours: A review

Abstract

We review the most recent and significant results published in the field of magnetotactic bacteria (MTB), in particular data relating to the use of bacterial magnetosomes in magnetic hyperthermia for the treatment of tumours. We review different methods for cultivating MTB and preparing suspensions of bacterial magnetosomes. As well as the production of magnetosomes, we also review key data on the toxicity of the magnetosomes as well as their heating and anti-tumour efficiencies. The toxicity and efficiency of magnetosomes needs to be understood and the risk–benefit ratio with which to evaluate their use in the magnetic hyperthermia treatment of tumours needs to be measured.     

Treatment with imatinib improves drug delivery and efficacy in NSCLC xenografts

Imatinib, an inhibitor of PDGF-Rbeta and other tyrosine kinase receptors, has been shown to decrease microvessel density and interstitial fluid pressure in solid tumours, thereby improving subsequent delivery of small molecules. The purpose of this study was to test whether pretreatment with imatinib increases the efficacy of traditional chemotherapy in mice bearing non-small cell lung carcinoma xenografts, and to investigate the effects of imatinib on liposomal drug delivery. Efficacy treatment groups included (n=9-10): saline control, imatinib alone (oral gavage, 100 mg kg(-1) x 7 days), docetaxel alone (10 mg kg(-1) i.p. 2 x /week until killing), and imatinib plus docetaxel (started on day 7 of imatinib). Tumours were monitored until they reached four times the initial treatment volume (4 x V) or 28 days. A separate experiment compared tumour doxorubicin concentrations (using high performance liquid chromatography) 24 h after treatment with liposomal doxorubicin alone (6 mg kg(-1) i.v., n=9) or imatinib plus liposomal doxorubicin (n=16). Imatinib plus docetaxel resulted in significantly improved antitumour efficacy (0/10 animals reached 4 x V by 28 days) when compared to docetaxel alone (3/9 reached 4 x V, P=0.014) or imatinib alone (9/10 reached 4 x V, P=0.025). Pretreatment with imatinib also significantly increased tumour concentrations of liposomal doxorubicin. Overall, these preclinical studies emphasise the potential of imatinib as an adjunct to small molecule or liposomal chemotherapy.