Multi-physics modeling of doxorubicine binding to ion-exchange resin in blood filtration devices

A group of drugs used in intra-arterial chemotherapy (IAC) have intrinsic ionic properties, which can be used for filtering excessive drugs from blood in order to reduce systemic toxicity. The ion-exchange mechanism is utilized in an endovascular Chemofilter device which can be deployed during the IAC for capturing ionic drugs after they have had their effect on the tumor. In this study, the concentrated solution theory is used to account for the effect of electrochemical forces on the drug transport and adsorption by introducing an effective diffusion coefficient in the advection–diffusion–reaction equation. Consequently, a multi-physics model coupling hemodynamic and electrochemical forces is developed and applied to simulations of the transport and binding of doxorubicine in the Chemofilter device. A comparison of drug adsorption predicted by the computations to that measured in animal studies demonstrated the benefits of using the concentrated solution theory over the Nernst–Plank relations for modeling drug binding.     

新辅助化疗对胃癌手术患者罗库溴铵药效学影响

目的:观察新辅助化疗对胃癌手术患者罗库溴铵药效学影响。方法:50例择期行开放胃癌根治术患者,ASA分级Ⅰ或Ⅱ,性别不限,年龄40～68岁,体质量56～79 kg,25例术前未做化疗（N组）,25例术前行新辅助化疗（C组）。静脉诱导患者入睡后,给予罗库溴铵0.9 mg/kg,当4次成串刺激（TOF）为0时插入气管导管,T1恢复至对照值25%时追加罗库溴铵0.15 mg/kg。记录罗库溴铵起效时间（给药至T1为0时间,t1）、首剂作用时间（首次给药至T1达25%时间,t2）、临床肌松时间（T1从0恢复至25%时间,t3）、恢复指数（T1从25%恢复至75%所需时间,RI）和拔管时间（停用肌松药至T4/T1恢复至90%时间,t4）和罗库溴铵的总用量。结果:与N组相比,C组肌松药首次作用时间延长,临床肌松时间延长,术中总用量减少,恢复指数和拔管时间延长（P<0.05）。两组患者起效时间无统计学差异（P>0.05）。结论:新辅助化疗可减少术中肌松药的使用量。     

膀胱癌化疗药物增敏机制研究进展

近年来化疗耐药严重制约着膀胱癌的治疗效果,术后复发率和转移率居高不下。因此,逆转膀胱癌化疗耐药性,寻找有效的化疗增敏靶点并探究其机制十分重要。目前临床上多采用经尿道膀胱肿瘤切除术,术后选择辅助化疗药物进行治疗,常用化疗药物包括顺铂、吉西他滨、阿霉素、表柔比星等。目前实现这些药物化疗增敏的靶点基因和分子在膀胱癌细胞中呈现不同的表达状态,且通过这些靶点实现增敏的机制也各有不同。本文将就膀胱癌化疗药物增敏靶点及机制的研究进展进行综述,以期为膀胱癌的化疗增敏探索新的思路。     

Synthesis and in vitro Anticancer Activity of Zinc(II) Phthalocyanines Conjugated with Coumarin Derivatives for Dual Photodynamic and Chemotherapy

The combination of photodynamic therapy and chemotherapy is a promising strategy to overcome growing problems in contemporary medicine, such as low therapeutic efficacy and drug resistance. Four zinc(II) phthalocyanine–coumarin conjugates were synthesized and characterized. In these complexes, zinc(II) phthalocyanine was used as the photosensitizing unit, and a coumarin derivative was selected as the cytostatic moiety; the two components were linked via a tri(ethylene glycol) chain. These conjugates exhibit high photocytotoxicity against HepG2 human hepatocarcinoma cells, with low IC₅₀ values in the range of 0.014–0.044 μM . The high photodynamic activities of these conjugates are in accordance with their low aggregation tendency and high cellular uptake. One of these conjugates exhibits high photocytotoxicity and significantly higher chemocytotoxicity. The results clearly show that the two antitumor components in these conjugates work in a cooperative fashion. As shown by confocal microscopy, the conjugates can localize in the mitochondria and lysosomes, and one of the conjugates can also localize in the cell nuclei.     

pH‐ and NIR Light‐Responsive Micelles with Hyperthermia‐Triggered Tumor Penetration and Cytoplasm Drug Release to Reverse Doxorubicin Resistance in Breast Cancer

The acquisition of multidrug resistance (MDR) is a major hurdle for the successful chemotherapy of tumors. Herein, a novel hybrid micelle with pH and near‐infrared (NIR) light dual‐responsive property is reported for reversing doxorubicin (DOX) resistance in breast cancer. The hybrid micelles are designed to integrate the pH‐ and NIR light‐responsive property of an amphiphilic diblock polymer and the high DOX loading capacity of a polymeric prodrug into one single nanocomposite. At physiological condition (i.e., pH 7.4), the micelles form compact nanostructure with particle size around 30 nm to facilitate blood circulation and passive tumor targeting. Meanwhile, the micelles are quickly dissociated in weakly acidic environment (i.e., pH ≤ 6.2) to release DOX prodrug. When exposed to NIR laser irradiation, the hybrid micelles can trigger notable tumor penetration and cytosol release of DOX payload by inducing tunable hyperthermia effect. In combination with localized NIR laser irradiation, the hybrid micelles significantly inhibit the growth of DOX‐resistant MCF‐7/ADR breast cancer in an orthotopic tumor bearing mouse model. Taken together, this pH and NIR light‐responsive micelles with hyperthermia‐triggered tumor penetration and cytoplasm drug release can be an effective nanoplatform to combat cancer MDR.     

The Application of Biomaterials in the Treatment of Platinum-Resistant Ovarian Cancer

More than 70 % of women with ovarian cancer are diagnosed with advanced-stage disease, which is initially treated with cytoreductive surgery, and combination chemotherapy with platinum-based compounds. Most patients initially respond to platinum-based therapy, but eventually up to 80 % of this responsive cohort becomes refractory due to the development of platinum resistance. This review discusses current and potential therapeutic approaches that exploit biomaterial-based applications to combat platinum resistance either by enhancing the delivery of platinum-based drugs or prodrugs, delivering other toxic non-platinum-based bioactive factors (by themselves or in combination with platinum-based drugs) or by delivering other bioactive factors that re-sensitize resistant ovarian cancer cells to these drugs. The types of materials that are used, the bioactive factors applied (i.e., drug or gene delivery), and the specific agents that are employed to target these types of cancer cells are discussed. We conclude that the unique attributes of biomaterial-based applications can be further explored toward overcoming platinum-resistant ovarian cancer as monotherapy, or in combination with other treatment strategies.     

Self‐Assembled Aptamer‐Nanomedicine for Targeted Chemotherapy and Gene Therapy

Chemotherapy is the mainstream treatment of anaplastic large cell lymphoma (ALCL). However, chemotherapy can cause severe adverse effects in patients because it is not ALCL‐specific. In this study, a multifunctional aptamer‐nanomedicine (Apt‐NMed) achieving targeted chemotherapy and gene therapy of ALCL is developed. Apt‐NMed is formulated by self‐assembly of synthetic oligonucleotides containing CD30‐specific aptamer and anaplastic lymphoma kinase (ALK)‐specific siRNA followed by self‐loading of the chemotherapeutic drug doxorubicin (DOX). Apt‐NMed exhibits a well‐defined nanostructure (diameter 59 mm) and stability in human serum. Under aptamer guidance, Apt‐NMed specifically binds and internalizes targeted ALCL cells. Intracellular delivery of Apt‐NMed triggers rapid DOX release for targeted ALCL chemotherapy and intracellular delivery of the ALK‐specific siRNA induced ALK oncogene silencing, resulting in combined therapeutic effects. Animal model studies reveal that upon systemic administration, Apt‐NMed specifically targets and selectively accumulates in ALCL tumor site, but does not react with off‐target tumors in the same xenograft mouse. Importantly, Apt‐NMed not only induces significantly higher inhibition in ALCL tumor growth, but also causes fewer or no side effects in treated mice compared to free DOX. Moreover, Apt‐NMed treatment markedly improves the survival rate of treated mice, opening a new avenue for precision treatment of ALCL.     

三维适形放疗配合腔内后装治疗宫颈癌的临床研究

Objective: The aim of our study was to evaluate the outcome and complications of cervical cancer patients undergoing conventional intracavitary brachytherapy (ICBT) treated with 3D-conformal radiotherapy (3DCRT). Methods: Sixty cervical cancer patients were divided randomly into the conformal group and the conventional group. Thirty patients treated with 3D-conformal radiotherapy in the 3DCRT group, when the whole pelvic received DT 40 Gy, a planning CT scan of each patient was obtained and the second 3DCRT therapy plan was taken. Then, continued to irradiate to 50 Gy. At last, 3DCRT was boosted at local involved volumes to the total close of 60 Gy. When 3DCRT was combined with intracavitary brachytherapy, the dose of brachytherapy to point A was 30 Gy/5 fractions. In the conventional group, after a total tumor dose of 40 Gy was delivered by the whole pelvic irradiation, the four-field technique was used to irradiate the total pelvic and regional nodes (median close of 10 Gy), and the involved volumes were boosted to 60 Gy and the dose of brachytherapy to point A was 30 Gy-36 Gy/5-6 fractions. Moreover, both groups were combined with intracavitary brachytherapy respectively. Results: The 1, 2, 3-year survival rates for the 3DCRT group and the conventional group were 96.7%, 93.3%, 90.0% and 86.6%, 76.7%,70% respectively (P = 0.04, P = 0.02 and P = 0.02). There was a statistically significant difference between the two groups.Compared to the two groups each other in toxic effects, except for the Ⅰ-Ⅱ grade rectal and bladder reaction and pelvic fibrosis which was lower in the 3DCRT group (P = 0. 007, P = 0. 006 and P = 0. 015), the side effects were similar and well tolerated in two groups. Conclusion: The all-course 3DCRT combined with intracavitary brachytherapy can be considered as an effective and feasible approach to cervical cancer and may significantly improve the survival rate and reduce the late toxicity. This new rote for 3DCRT merits need further evaluation with large patient numbers and longer follows up.     

乳腺癌新辅助化疗前后HER-2表达的变化

Objective: The aim of this study was to study changes of HER-2 expression after neoadjuvant chemotherapy in the breast cancer cases. Methods: One hundred and thirty-seven female patients with primary breast cancers, who received neoadjuvant chemotherapy, underwent core needle puncture and Mammotome biopsy before chemotherapy, and the biopsy results were used as the basis of histological diagnosis, fluorescence in situ hybridization (FISH) was performed to test HER 2 status of tumor tissues before and after chemotherapy. All patients underwent FEC, TE, or AC neoadjuvant chemotherapy of 2-6 cycles before surgery. Results: Twenty-two patients were positive according to FISH test among 137 preoperative patients, 8 patients achieved pathological complete remission after chemotherapy (three HER-2 positive patients and five negative patients), 91 patients achieved partial remission, 24 patients were stable, and 14 cases were invalid. Twenty-two patients were positive according to FISH test (8 patients with pathological complete remission did not undergo test), and positive patients still expressed positively after chemotherapy before neoadjuvant chemotherapy. Three negative patients were converted to be positive, and changes before and after chemotherapy had no statistical difference (P > 0.05). Conclusion: Neoadjuvant chemotherapy makes no influence on patients with HER-2 positive expression, while patients with negative expression can be converted to be positive, but without significant difference.