Compressed polymeric mini-matrices for drug release control

Matrices of reduced dimensions of either inert or swellable polymers for multiple-unit administration, containing diprophylline as the model drug, were made by compression. Some swellable mini-matrices prepared from poly(vinyl alcohol) were externally crosslinked by soaking in an acidic formalin solution, and subsequent drying and exposure to UV or thermal energy sources. The release kinetics of the model drug from the mini-matrices was investigated by analyzing the early time portion of the release curves according to a simplified exponential equation which allows the comprehension of the release mechanism. The results showed that the release kinetics may be Fickian or anomalous nonFickian depending on the solubility of the polymer employed. Zero-order release kinetics were obtained by using mini-matrices, which were crosslinked at the surface.     

Disulfide bond based polymeric drug carriers for cancer chemotherapy and relevant redox environments in mammals

Increasing numbers of disulfide linkage‐employing polymeric drug carriers that utilize the reversible peculiarity of this unique covalent bond have been reported. The reduction‐sensitive disulfide bond is usually employed as a linkage between hydrophilic and hydrophobic polymers, polymers and drugs, or as cross‐linkers in polymeric drug carriers. These polymeric drug carriers are designed to exploit the significant redox potential difference between the reducing intracellular environments and relatively oxidizing extracellular spaces. In addition, these drug carriers can release a considerable amount of anticancer drug in response to the reducing environment when they reach tumor tissues, effectively improving antitumor efficacy. This review focuses on various disulfide linkage‐employing polymeric drug carriers. Important redox thiol pools, including GSH/GSSG, Cys/CySS, and Trx1, as well as redox environments in mammals, will be introduced.     

Nuclear drug delivery for cancer chemotherapy

Nanosystems with unique physical and biological properties have been extensively explored for cancer targeted intracellular delivery of small-molecular chemotherapeutic drugs to increase their therapeutic efficacies and to minimize their side effects. A large number of anticancer drugs are DNA-toxins that bind nuclear DNA or its associated enzymes to exert their cytotoxicity to cancer cells. After entering tumor cells, they need to be further delivered to the nucleus for actions. Herein, we discuss the biological barriers and summarize recent progress of nuclear drug delivery for cancer chemotherapy, emphasizing strategies that appear useful for design of vehicles capable of delivering drugs to the nucleus, particularly for in vivo applications. The existing obstacles or problems that need to be overcome before successful applications of nuclear drug delivery for cancer chemotherapy are also discussed.     

Peptides in cancer nanomedicine: drug carriers, targeting ligands and protease substrates

Peptides are attracting increasing attention as therapeutic agents, as the technologies for peptide development and manufacture continue to mature. Concurrently, with booming research in nanotechnology for biomedical applications, peptides have been studied as an important class of components in nanomedicine, and they have been used either alone or in combination with nanomaterials of every reported composition. Peptides possess many advantages, such as smallness, ease of synthesis and modification, and good biocompatibility. Their functions in cancer nanomedicine, discussed in this review, include serving as drug carriers, as targeting ligands, and as protease-responsive substrates for drug delivery.     

Molecular design of biodegradable polymeric micelles for temperature-responsive drug release.

We designed thermo-responsive and biodegradable polymeric micelles for an ideal drug delivery system whose target sites are where external stimuli selectively release drugs from the polymeric micelles. The thermo-responsive micelles formed from block copolymers that were composed both of a hydrophobic block and a thermo-responsive block. Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) showing a lower critical solution temperature (LCST) around 40 degrees C was synthesized for the thermo-responsive block, while biodegradable poly(D,L-lactide), poly(epsilon-caprolactone), or poly(D,L-lactide-co-epsilon-caprolactone) was used for the hydrophobic block. By changing both the block lengths of the poly(D,L-lactide)-containing block copolymers, physical parameters such as micelle diameter and critical micelle concentration were varied. On the other hand, the choice of the hydrophobic block was revealed to be critical in relation to both on the thermo-responsive release of the incorporated anti-cancer drug, doxorubicin, and the temperature-dependent change of the hydrophobicity of the micelles' inner core. One polymeric micelle composition successfully exhibited rapid and thermo-responsive drug release while possessing a biodegradable character.     

Therapeutic drug monitoring in antituberculosis chemotherapy: clinical perspectives.

BACKGROUND: Therapeutic drug monitoring (TDM) represents an area where multidisciplinary service is rendered for optimization of clinical care, through enabling maximum drug therapeutic efficacy and minimum drug toxicity. This is a recently developed field for antituberculosis chemotherapy. The other goals of TDM principally include study and management of pharmacokinetic drug-drug and drug-disease interactions as well as the evaluation of new fixed-dose combinations (FDC) developed for treatment of tuberculosis. CONCLUSION: In the years to come, with the advancement in knowledge, technology and expertise, it is hoped that TDM, as a novel paradigm of care in tuberculosis, may gain expanding indications and reach a new horizon.     

Spermine modified polymeric micelles with pH-sensitive drug release for targeted and enhanced antitumor therapy

Tumor targeting delivery of chemotherapeutic drugs by nanocarriers has been demonstrated to be a promising strategy for cancer therapy with improved therapeutic efficacy. In this work, we reported a novel type of active targeting micelle with pH-responsive drug release by using biodegradable poly(lactide)-poly(2-ethyl-2-oxazoline) di-block copolymers functionalized with spermine (SPM). SPM has been considered as a tumor binding ligand through its specific interaction with the polyamine transport system (PTS), a transmembrane protein overexpressed on various types of cancer cell, while its application in nano-drug delivery systems has rarely been explored. The micelles with spherical shape (∼110 nm) could load hydrophobic paclitaxel (PTX) with high capacity, and release the payload much faster at acidic pH (4.5–6.5) than at pH 7.4. This pH-responsive property assisted the rapid escape of drug from the endo/lysosome after internalization as demonstrated by confocal laser scanning microscopy images using coumarin-6 (Cou-6) as a fluorescent probe. With surface SPM modification, the micelles displayed much higher cellular uptake than SPM lacking micelles in various types of cancer cells, demonstrating tumor targeting ability. The uptake mechanism of SPM modified micelles was explored by flow cytometry, which suggested an energy-consuming sag vesicle-mediated endocytosis pathway. As expected, the micelles displayed significantly enhanced anti-cancer activity. This work demonstrates that SPM modified pH-sensitive micelles may be potential drug delivery vehicles for targeting and effective cancer therapy.

Tumor targeting delivery of SPM functionalized micelles via PTS binding and their endocytosis and pH-triggered endo/lysosome drug release for anti-cancer therapy.     

Biodegradable porous polymeric drug as a drug delivery system: alleviation of doxorubicin-induced cardiotoxicity via passive targeted release

Doxorubicin (DOX) is an effective chemotherapeutic drug developed against a broad range of cancers, and its clinical applications are greatly restricted by the side effects of severe cardiotoxicity during tumour treatment. Herein, the DOX-loaded biodegradable porous polymeric drug, namely, Fc-Ma-DOX, which was stable in the circulation, but easy to compose in the acidic medium, was used as the drug delivery system avoiding the indiscriminate release of DOX. Fc-Ma was constructed via the copolymerization of 1,1′-ferrocenecarbaldehyde with d-mannitol (Ma) through the pH-sensitive acetal bonds. Echocardiography, biochemical parameters, pathological examination, and western blot results showed that DOX treatment caused increased myocardial injury and oxidative stress damage. In contrast, treatment with Fc-Ma-DOX significantly reduced myocardial injury and oxidative stress by DOX treatment. Notably, in the Fc-Ma-DOX treatment group, we observed a significant decrease in the uptake of DOX by H9C2 cells and a significant decrease in reactive oxygen species (ROS) production.

Alleviation of doxorubicin-induced cardiotoxicity by a biodegradable porous organic polymer drug delivery system via passive targeted release.     

A model of dissolution-controlled,diffusional drug release from non-swellable polymeric microspheres

A new model was developed to account for the kinetics of drug release from porous, non-swellable polymeric microparticles in the case where both drug dissolution and diffusion mechanisms control the overall release process. The model incorporates a linear first-order dissolution term and the transient Fickian diffusion equation, and is solved for perfect sink and surface-dependent boundary conditions. Long-term limiting solutions indicate that after an initial time-dependent period of release, the release rate becomes independent of time. Numerical solutions are provided which indicate the effects of particle size, solute diffusion coefficient and solute dissolution rate on the release kinetics.     

膜缓控释给药系统促进损伤组织的修复

背景：目前研究多注重缓控释给药膜的缓控释效果及其生物相容性,也有开展缓控释给药膜参与损伤组织修复的机制研究,其中干细胞是损伤组织修复的关键因素,但干细胞与缓控释给药膜之间的联系尚未得到足够关注。目的：分析膜缓控释给药系统在组织损伤修复中的研究现状与进展。方法：以“缓释系统,膜,药物载体,组织损伤修复,干细胞归巢;sustained-releasesystem,membrane,drugdelivery,injuriesandrepairsoftissue,stemcellhoming”为关键词,采用计算机检索Pubmed数据库、中国知网、Elsevier数据库1992年1月至2012年12月有关膜缓控释给药系统临床应用及实验研究的文章。结果与结论：在膜缓控释给药系统中高分子材料几乎成了药物和生长因子在传递、渗透过程中不可分割的组成部分。虽然药物缓释系统的发展与制膜技术都在不断的更新,但距离完全达到理想的应用标准还有一定的差距,如不具备主动吸引干细胞定向迁移与分布的生物学功能。近年来膜缓控释给药系统出现新的发展方向,即不仅能起到诱导干细胞定向分化的作用,也能诱导干细胞向损伤部位定向分布,从而促进损伤组织再生修复。     

Functional polymeric dialdehyde dextrin network capped mesoporous silica nanoparticles for pH/GSH dual-controlled drug release

Multi-stimulation responsive nanomaterial-based drug delivery systems promise enhanced therapeutic efficacy in cancer therapy. This work examines a smart pH/GSH dual-responsive drug delivery system by using dialdehyde dextrin (DAD) end-capped mesoporous silica nanoparticles (MSNs). Specifically, DAD was applied as a “gatekeeper polymer” agent to seal drug loads inside the mesoporous of MSNs via a pH-sensitive Schiff bond, whereas the formed DAD polymer shells were further cross-linked by GSH-sensitive disulfide bonds. Results revealed that the DAD gatekeeper polymer could tightly close the mesopores of MSNs to control premature drug release under physiological conditions and respond to acidic and GSH conditions to release the trapped drugs. Significantly, fluorescent microscopy observation and cytotoxicity studies indicated that drug-loaded nanoparticles could be rapidly internalized through a passive targeting effect to inhibit cancer growth. Taken together, these polymer-modified pH/GSH dual-responsive MSNs could be used as promising candidates for “on-demand” anticancer drug delivery applications.

A smart pH/GSH dual-responsive drug delivery system by using DAD as a “gatekeeper polymer” to end-cap MSNs via pH-sensitive Schiff bond, whereas DAD polymer shell were cross-linked by GSH-sensitive disulfide bond.     

Dual targeted and pH-responsive gold nanorods with improved chemotherapy and photothermal ablation for synergistic cancer treatment

Cancer is considered to be one of the leading causes of morbidity and mortality worldwide. A multifunctional nanosystem based on gold nanorods (GNRs) has demonstrated the potential to enhance therapeutic performance. In this research, dual-targeted pH-responsive GNRs for synergistic cancer treatment were developed and investigated. The GNRs could target angiogenic endothelial cells in the tumor region using αvβ3-mediated recognition and subsequently facilitate its specific binding to tumor cells mediated via recognition of the folate receptor, which could accumulate precisely at the tumor site. Doxorubicin (DOX) was loaded on to the surface of GNRs via a pH-sensitive hydrazone (hz) bond, which could effectively control the drug release by responding to the tumor acidic microenvironment. In vitro, the FA/RGD-DOX-hz-GNRs showed higher tumor specificity and killing ability under near-infrared irradiation. Furthermore, in B16-F10 xenograft tumor-bearing mice, FA/RGD-DOX-hz-GNRs produced the optimal tumor therapeutic efficacy by antagonizing angiogenesis, inhibiting cell proliferation and causing necrosis. Therefore, the strategy of integration of a photothermal effect, chemotherapy and a molecular active targeting based double-targeting mode appeared advantageous over chemotherapy or a photothermal therapy alone.

A dual-targeted pH-responsive GNR for synergistic cancer treatment was developed and investigated, which demonstrated the desired potential for enhancing therapeutic performance.     

Non-protein bound iron release during chemotherapy in cancer patients

Non-protein bound iron (NPBI) is able to catalyse oxidative reactions, causing damage to vital structures. Adverse effects induced by cisplatin seem, in part, to be mediated by free radicals. In the present study, we have measured plasma NPBI, various other iron parameters and antioxidants in 28 cancer patients undergoing cisplatin-based chemotherapy at various time points before and during chemotherapy. No NPBI was present prior to therapy, but within 1-4 days following the first administration of chemotherapy, mean NPBI rose significantly to 10.6+/-6.6 micromol/l (range, 0.6-21.3 micromol/l) in 18 (64.3%) of the 28 patients measured. The rise in NPBI was accompanied by a significant rise in total plasma iron and ferritin and a marked decrease in the latent iron-binding capacity. Concomitantly, plasma vitamins C and E decreased significantly, indicating consumption of antioxidants. Similar observations were also made during the fourth chemotherapy cycle. The increase in NPBI preceded and correlated significantly with chemotherapy toxicity, such as a decrease in leucocyte count and haemoglobin, with a transient rise in various liver enzymes and with known cisplatin-related toxicity, i.e. the loss of renal and hearing function. In conclusion, cisplatin chemotherapy induces oxidative damage which rapidly leads to release of iron from intracellular proteins and the appearance of NPBI. Bone marrow, red blood cells, liver and kidney seem to be a likely source of NPBI. The observed high levels of NPBI may be a major causative determinant in chemotherapy-induced toxicity.     

重组人血管内皮抑制素联合化疗治疗晚期乳腺癌疗效观察

目的探讨重组人血管内皮抑素联合TC方案（多西紫杉醇＋环磷酰胺）治疗晚期乳腺癌的近期疗效、安全性,观察治疗前、后血清血管内皮生长因子（vascular endothelial growth factor,VEGF）水平变化。方法晚期乳腺癌患者56例,随机分为观察组和治疗组各28例,治疗组应用TC方案化疗,观察组在治疗组基础上给予重组人血管内皮抑素,2组均21d为1个周期,治疗2个周期后评价不良反应与疗效。分别于治疗前及治疗2个周期后检测2组血清VEGF水平,并与同期28例健康体检者（对照组）比较。结果观察组有效率（75．0％）高于治疗组（46．4％）（P〈0．05）,骨髓抑制、恶心呕吐、脱发发生率与治疗组比较差异无统计学意义（P〉0．05）;观察组、治疗组治疗前血清VEGF水平均高于对照组（P〈0．05）,观察组治疗后血清VEGF水平低于治疗前与治疗组（P〈0．05）,治疗组治疗后血清VEGF水平与治疗前比较差异无统计学意义（P〉0．05）。结论重组人血管内皮抑制素联合TC方案治疗晚期乳腺癌可提高疗效,降低血清VEGF水平,且不增加化疗的不良反应。     

Glucose-sensitive polymeric matrices for controlled drug delivery

Hydrogel matrices were prepared by chemical polymerization of solutions containing 2-hydroxyethyl methacrylate, N,N-dimethyl-aminoethyl methacrylate, tetraethylene glycol dimethacrylate, ethylene glycol and water solutions containing glucose oxidase, bacitracin or insulin. The hydrogels displayed faster and higher swelling and release rates at lower pH or at higher glucose concentrations. Swelling and release kinetics were also responsive to step changes in glucose concentration in the physiological range. The kinetics of the soluble and immobilized enzyme followed Michaelis Menten's kinetics. In the soluble state the enzyme was more active than the immobilized one due to mass transfer limitations, which may be overcome by preparation of microbead configuration.     

卵巢上皮癌TCI化疗方案的疗效研究及远期预后探讨

目的探讨TCI联合化疗方案对于卵巢上皮癌的疗效及远期预后。方法 2000年2月~2010年12月在本院进行规范治疗的卵巢上皮癌158例,运用TCI治疗方案为88例,其化疗方案为TP和/或CAP和/或IAP（简称TCI方案）;对照组治疗70例,方案选择为PC（环磷酰胺与顺铂）,比较两组的临床缓解情况、毒性反应及远期预后,并且对TCI组进行COX系统回归因素分析。结果 TCI治疗组总体缓解率明显高于对照组,毒性反应方面TCI治疗组的血液系统及神经系统不良反应均显著低于PC组,胃肠道不良反应与心血管系统反应则无显著差异;TCI组5年平均生存率为31.2%,病理分期Ⅰ、Ⅱ、Ⅲ、Ⅳ期中位生存时间分别是79、56、22、18个月,残留灶小于2 cm者和治疗次数大于6次者远期预后明显好与相对应者。结论 TCI化疗方案显著优于PC方案,且不良反应相对较少,但胃肠道反应应引起重视,在预后各种因素方面病理分期、术后残留及疗程多少均具有一定相关意义。     

Highly-controllable drug release from core cross-linked singlet oxygen-responsive nanoparticles for cancer therapy

Highly-controllable release consisting of preventing unnecessary drug leakage at physiologically normal tissues and triggering sufficient drug release at tumor sites is the main aim of nanoparticle-based tumor therapy. Developing drug-conjugation strategies with covalent bonds in response to a characteristic stimulus, such as reactive oxygen species (ROS) generated by photodynamic therapy (PDT) has attracted much attention. ROS can not only cause cytotoxicity, but also trigger the cleavage of ROS-responsive linkers. Therefore, it is feasible to design a new model of controlled drug release via the breakage of ROS-responsive linkers and degradation of nanoparticles. The self-supply of the stimulus and highly-controllable drug release can be achieved by encapsulation of photosensitizer (PS) and chemotherapeutic drugs simultaneously without any support of tumor endogenous stimuli. Therefore, we used thioketal (TK) linkers as the responsive linkers due to their reaction with singlet oxygen (¹O₂, SO), a type of ROS. They were conjugated to the side groups of polyphosphoesters (PPE) via click chemistry to acquire the core cross-linked SO-responsive PPE nanoparticles poly(thioketal phosphoesters) (TK-PPE). TK-PPE coated with the photosensitizer chlorin e6 (Ce6) and chemotherapeutic drug doxorubicin (DOX) simultaneously were prepared and named as TK-PPE_Ce6&DOX. TK-PPE_Ce6&DOX kept stable due to the high stability of the TK-linkers in the normal physiological environment. With self-production of SO as the stimulating factor from the encapsulated Ce6, highly-controlled drug release was achieved. After incubation of tumor cells, 660 nm laser irradiation induced SO generation, resulting in the cleavage of TK-linkers and boosted-release of DOX. Highly-controllable drug release of TK-PPE_Ce6&DOX through self-production of stimulus increased antitumor efficacy, offering a promising avenue for clinical on-demand chemotherapy.

Core cross-linked singlet oxygen-responsive nanoparticle TK-PPE_Ce6&DOX could achieve highly-controllable drug release through self-production of SO as the stimulus to increase antitumor efficacy for cancer therapy.