Prediction of convection-enhanced drug delivery to the human brain

The treatment for many neurodegenerative diseases of the central nervous system (CNS) involves the delivery of large molecular weight drugs to the brain. The blood brain barrier, however, prevents many therapeutic molecules from entering the CNS. Despite much effort in studying drug dispersion with animal models, accurate drug targeting in humans remains a challenge. This article proposes an engineering approach for the systematic design of targeted drug delivery into the human brain. The proposed method predicts achievable volumes of distribution for therapeutic agents based on first principles transport and chemical kinetics models as well as accurate reconstruction of the brain geometry from patient-specific diffusion tensor magnetic resonance imaging. The predictive capabilities of the methodology will be demonstrated for invasive intraparenchymal drug administration. A systematic procedure to determine the optimal infusion and catheter design parameters to maximize penetration depth and volumes of distribution in the target area will be discussed. The computational results are validated with agarose gel phantom experiments. The methodology integrates interdisciplinary expertise from medical imaging and engineering. This approach will allow physicians and scientists to design and optimize drug administration in a systematic fashion.     

Coordination conjugates of therapeutic proteins with drug carriers: a new approach for versatile advanced drug delivery

We present here a general system for the coordination attachment of therapeutic proteins to a drug delivery system and its application in combined therapy. Proof of concept is demonstrated by the synthesis and testing of the targeted drug delivery system for cytostatics, which is based on a combination of the drug carrier Zn-porphyrin-cyclodextrin conjugates and their supramolecular coordination complexes with immunoglobulins. This system can be as readily used for a variety of therapeutic and targeting proteins including PAs, MAs, lectins, and HSA. Moreover, it allows combined photodynamic therapy, cell targeted chemotherapy and immunotherapy. When tested in a mouse model with human C32 carcinoma, the therapeutic superiority of the coordination assembly nanosystem was shown in comparison with the efficacy of building blocks used for the construction of the system.     

Cancer hallmarks and malignancy features: Gateway for improved targeted drug delivery

Cancer chemotherapy is mainly based on the use of cytotoxic compounds that often affect other tissues, generating serious side effects which deteriorate the quality of life of patients. Recent advancements in targeted drug delivery systems offer opportunities to improve the efficiency of chemotherapy, by the use of smaller drug doses with reduced side effects. In the gene therapy approach, this consists in improving the transformation potential of the gene delivery system. Interestingly, these systems further provide good platforms for the delivery of hydrophobic and low-bioavailability compounds, while facilitating the penetration of the blood-brain barrier. The present report provides an overview of biologically relevant cancer hallmarks that can be exploited to design effective delivery vehicles that release cytotoxic compounds specifically in cancer tissues, in a targeted manner. The relevance of each cancer marker is presented, with particular emphasis on the generation of these hallmarks and their importance in cancer cell biology.     

促凋亡基因Bax在胰腺癌中的研究进展

胰腺癌的恶性程度高、转移早、浸润性强,这与胰腺癌的细胞凋亡异常有密切的关系。Bax是目前研究最深入的促凋亡基因之一。多数研究认为,Bax在胰腺癌中存在高表达,其表达率从53%到100%不等。有研究认为Bax的表达预示着胰腺癌的良性预后,也有研究发现胰腺癌中Bax的表达与胰腺癌的分级分化等有关。Bax在胰腺癌中的表达受p53、PERIOD1、P13K/AKT等的调控。Bax表达异常及其突变可能与胰腺癌的发生有关。研究发现Bax表达可增强胰腺癌对吉西他滨和5-FU等化疗药物以及放射治疗的敏感性,而Bax/Bcl-2的比值可能与胰腺癌放化疗敏感性更相关。提高Bax基因表达、上调Bax活性等针对Bax的靶向治疗已显示出促进胰腺癌细胞凋亡、增强药物抗癌效应的作用。同时,作为最重要的促凋亡蛋白之一,Bax成为评价各种抗胰腺癌药物的疗效、探讨其作用机制的重要指标之一。对胰腺癌中Bax的深入研究,有利于了解其与胰腺癌的预后和耐药性的关系,为胰腺癌的靶向治疗提供新的方向。     

Targeted delivery of antibody conjugated liposomal drug carriers to rat myocardial infarction

Immunoliposome (IL) targeting to areas of inflammation after an acute myocardial infarction (MI) could provide the means by which pro-angiogenic compounds can be selectively targeted to the infarcted region. The adhesion of model drug carriers and ILs coated with an antibody to P-selectin was quantified in a rat model of MI following left coronary artery ligation. Anti-P-selectin coated model drug carriers showed a 140% and 180% increase in adhesion in the border zone of the MI 1 and 4 h post-MI, respectively. Radiolabeled anti-P-selectin ILs injected immediately post-MI and allowed to circulate 24 h showed an 83% increase in targeting to infarcted myocardium when compared to adjacent non-infarcted myocardium. Radiolabeled anti-P-selectin ILs injected 4 h post-MI and allowed to circulate for 24 h showed a 92% increase in accumulation in infarcted myocardium when compared to adjacent non-infarcted myocardium. Targeting to upregulated adhesion molecules on the endothelium provides a promising strategy for selectively delivering compounds to the infarct region of the myocardium using our liposomal-based drug delivery vehicle.     

Targeted delivery of atorvastatin via asialoglycoprotein receptor (ASGPR)

Targeted drug delivery platforms can increase the concentration of drugs in specific cell populations, reduce adverse effects, and hence improve the therapeutic effect of drugs. Herein, we designed two conjugates by installing the targeting ligand GalNAc (N-acetylgalactosamine) onto atorvastatin (AT). Compared to the parent drug, these two conjugates, termed G2-AT and G2-K-AT, showed increased hepatic cellular uptake. Moreover, both conjugates were able to release atorvastatin, and consequently showed dramatic inhibition of β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) reductase and increased LDL receptors on cell surface.     

Chimeric aptamers in cancer cell-targeted drug delivery

Aptamers are single-stranded structured oligonucleotides (DNA or RNA) that can bind to a wide range of targets (“apatopes”) with high affinity and specificity. These nucleic acid ligands, generated from pools of random-sequence by an in vitro selection process referred to as systematic evolution of ligands by exponential enrichment (SELEX), have now been identified as excellent tools for chemical biology, therapeutic delivery, diagnosis, research, and monitoring therapy in real-time imaging. Today, aptamers represent an interesting class of modern pharmaceuticals which with their low immunogenic potential mimic extend many of the properties of monoclonal antibodies in diagnostics, research, and therapeutics. More recently, chimeric aptamer approach employing many different possible types of chimerization strategies has generated more stable and efficient chimeric aptamers with aptamer–aptamer, aptamer–nonaptamer biomacromolecules (siRNAs, proteins) and aptamer–nanoparticle chimeras. These chimeric aptamers when conjugated with various biomacromolecules like locked nucleic acid (LNA) to potentiate their stability, biodistribution, and targeting efficiency, have facilitated the accurate targeting in preclinical trials. We developed LNA-aptamer (anti-nucleolin and EpCAM) complexes which were loaded in iron-saturated bovine lactofeerin (Fe-blf)-coated dopamine modified surface of superparamagnetic iron oxide (Fe₃O₄) nanoparticles (SPIONs). This complex was used to deliver the specific aptamers in tumor cells in a co-culture model of normal and cancer cells. This review focuses on the chimeric aptamers, currently in development that are likely to find future practical applications in concert with other therapeutic molecules and modalities.     

Targeting of herbal bioactives through folate receptors: a novel concept to enhance intracellular drug delivery in cancer therapy

Targeted drug delivery through folate receptor (FR) has emerged as a most biocompatible, target oriented, and non-immunogenic cargoes for the delivery of anticancer drugs. FRs are highly overexpressed in many tumor cells (like ovarian, lung, breast, kidney, brain, endometrial, and colon cancer), and targeting them through conjugates bearing specific ligand with encapsulated nanodrug moiety is undoubtedly, a promising approach toward tumor targeting. Folate, being an endogenous ligand, can be exploited well to affect various cellular events occurring during the progress of tumor, in a more natural and definite way. Thus, the aim of the review lies in summarizing the advancements taken place in the drug delivery system of different therapeutics through FRs and to refine its role as an endogenous ligand, in targeting of synthetic as well as natural bioactives. The review also provides an update on the patents received on the folate-based drug delivery system.     

Cyclodextrins in drug delivery: An updated review

The purpose of this review is to discuss and summarize some of the interesting findings and applications of cyclodextrins (CDs) and their derivatives in different areas of drug delivery, particularly in protein and peptide drug delivery and gene delivery. The article highlights important CD applications in the design of various novel delivery systems like liposomes, microspheres, microcapsules, and nanoparticles. In addition to their well-known effects on drug solubility and dissolution, bioavailability, safety, and stability, their use as excipients in drug formulation are also discussed in this article. The article also focuses on various factors influencing inclusion complex formation because an understanding of the same is necessary for proper handling of these versatile materials. Some important considerations in selecting CDs in drug formulation such as their commercial availability, regulatory status, and patent status are also summarized. CDs, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different novel drugs through different delivery routes. Published: October 14, 2005     

Proteomic strategies in the search for novel pancreatic cancer biomarkers and drug targets: recent advances and clinical impact

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers; despite a low incidence rate it is the fourth leading cause of cancer-related death in the world. Improvement of the diagnosis, prognosis and treatment remains the main focus of pancreatic cancer research. Rapid developments in proteomic technologies has improved our understanding of the pancreatic cancer proteome. Here, the authors summarise the recent proteomic strategies undertaken in the search for: novel biomarkers for early diagnosis, pancreatic cancer-specific proteins which may be used for novel targeted therapies and proteins which may be useful for monitoring disease progression post-therapy. Recent advances and findings discussed here provide great promise of having a significant clinical impact and improving the outcome of patients with this malignancy.     

Nanotechnology-based intelligent drug design for cancer metastasis treatment

Traditional chemotherapy used today at clinics is mainly inherited from the thinking and designs made four decades ago when the Cancer War was declared. The potency of those chemotherapy drugs on in-vitro cancer cells is clearly demonstrated at even nanomolar levels. However, due to their non-specific effects in the body on normal tissues, these drugs cause toxicity, deteriorate patient's life quality, weaken the host immunosurveillance system, and result in an irreversible damage to human's own recovery power. Owing to their unique physical and biological properties, nanotechnology-based chemotherapies seem to have an ability to specifically and safely reach tumor foci with enhanced efficacy and low toxicity. Herein, we comprehensively examine the current nanotechnology-based pharmaceutical platforms and strategies for intelligent design of new nanomedicines based on targeted drug delivery system (TDDS) for cancer metastasis treatment, analyze the pros and cons of nanomedicines versus traditional chemotherapy, and evaluate the importance that nanomaterials can bring in to significantly improve cancer metastasis treatment.     

Functions and clinical implications of exosomes in pancreatic cancer

Pancreatic cancer is one of the most aggressive human malignancies and is associated with a dismal prognosis, which can be contributed to its atypical symptoms, metastatic propensity, and significant chemoresistance. Emerging evidence shows that pancreatic cancer cell-derived exosomes (PEXs) play critical roles in tumorigenesis and tumor development, as they are involved in drug resistance, immune evasion and metabolic reprograming, and distant metastasis of pancreatic cancer. Their numerous differentially expressed and functional contents make PEXs promising screening tools and therapeutic targets, which require further exploration. In this review, we focus on the functions of PEX contents and their clinical implications in pancreatic cancer.     

非侵入性脑内给药

血脑屏障使许多具有中枢神经活性的药物无法到达脑部发挥作用,非侵入性脑内给药因对机体无创伤而受到研究者广泛关注。本文介绍了血脑屏障的物质转运系统以及经鼻粘膜、渗透性血脑屏障开放、纳米粒载体和转运载体法等非侵入性脑内给药方法的机制和特点。     

Conformationally constrained peptides for drug delivery

Peptides have shown great potential in acting as template for developing versatile carrier platforms in nanomedicine, aimed at selective delivery of drugs to only pathological tissues saving its normal neighbors. Cell‐penetrating peptides (CPPs) are short oligomeric peptides capable of translocating across the cell membrane while simultaneously employing multiple mechanisms of entry. Most CPPs exist as disordered structures in solution and may adopt a helical conformation on interaction with cell membrane, vital to their penetrative capability. Herein, we report a series of cationic helical amphipathic peptides (CHAPs), which are topologically constrained to be helical. The peptides were tested against cervical and breast cancer cells for their cell penetration and drug delivery potential. The cellular uptake of CHAP peptides is independent of temperature and energy availability. The activity of the peptides is biocompatible in bovine serum. CHAPs delivered functional methotrexate (MTX) inside the cell as CHAP‐MTX conjugates. CHAP‐MTX conjugates were more toxic to cancer cells than MTX alone. However, the CHAP‐MTX conjugates were less toxic to HEK‐293 cells compared with the cancer cells suggesting higher affinity towards cancer cells.     

5-Fu小剂量泵二线治疗晚期胰腺癌的临床研究

目的观察5-Fu小剂量泵二线治疗晚期胰腺癌的疗效和不良反应。方法 13例晚期吉西他滨治疗失败的胰腺癌患者,5-Fu300mg/d,1～14d持续静脉泵入,DDP5mg1～5d,8～12d静点,28d为1周期。观察客观疗效、临床获益率及不良反应。结果部分缓解1例,稳定6例,10例临床获益,中位生存期5.8个月（2.2～8.3个月）,中位疾病进展时间3.0个月（1～4.5个月）,主要不良反应为菌群失调相关性腹泻。结论 5-Fu小剂量泵二线治疗可改善晚期胰腺癌患者生存,耐受性好。     

Gold nanoparticles: Emerging paradigm for targeted drug delivery system

The application of nanotechnology in medicine, known as nanomedicine, has introduced a plethora of nanoparticles of variable chemistry and design considerations for cancer diagnosis and treatment. One of the most important field is the design and development of pharmaceutical drugs, based on targeted drug delivery system (TDDS). Being inspired by physio-chemical properties of nanoparticles, TDDS are designed to safely reach their targets and specifically release their cargo at the site of disease for enhanced therapeutic effects, thereby increasing the drug tissue bioavailability. Nanoparticles have the advantage of targeting cancer by simply being accumulated and entrapped in cancer cells. However, even after rapid growth of nanotechnology in nanomedicine, designing an effective targeted drug delivery system is still a challenging task. In this review, we reveal the recent advances in drug delivery approach with a particular focus on gold nanoparticles. We seek to expound on how these nanomaterials communicate in the complex environment to reach the target site, and how to design the effective TDDS for complex environments and simultaneously monitor the toxicity on the basis of designing such delivery complexes. Hence, this review will shed light on the research, opportunities and challenges for engineering nanomaterials with cancer biology and medicine to develop effective TDDS for treatment of cancer.     

Numerical simulation of iontophoresis in the drug delivery system

The architecture and composition of stratum corneum act as barriers and limit the diffusion of most drug molecules and ions. Much effort has been made to overcome this barrier and it can be seen that iontophoresis has shown a good effect. Iontophoresis represents the application of low electrical potential to increase the transport of drugs into and across the skin or tissue. Iontophoresis is a noninvasive drug delivery system, and therefore, it is a useful alternative to drug transportation by injection. In this study, we present a numerical model and effects of electrical potential on the drug diffusion in the buccal tissue and the stratum corneum. The initial numerical results are in good comparison with experimental observation. We demonstrate that the application of an applied voltage can greatly improve the efficacy of localized drug delivery as compared to diffusion alone.     

Zwitterionic polymers in drug delivery: A review

Developments of novel drug delivery vehicles are sought-after to augment the therapeutic effectiveness of standard drugs. An urgency to design novel drug delivery vehicles that are sustainable, biocompatible, have minimized cytotoxicity, no immunogenicity, high stability, long circulation time, and are capable of averting recognition by the immune system is perceived. In this pursuit for an ideal candidate for drug delivery vehicles, zwitterionic materials have come up as fulfilling almost all these expectations. This comprehensive review is presenting the progress made by zwitterionic polymeric architectures as prospective sustainable drug delivery vehicles. Zwitterionic polymers with varied architecture such as appending protein conjugates, nanoparticles, surface coatings, liposomes, hydrogels, etc, used to fabricate drug delivery vehicles are reviewed here. A brief introduction of zwitterionic polymers and their application as reliable drug delivery vehicles, such as zwitterionic polymer–protein conjugates, zwitterionic polymer-based drug nanocarriers, and stimulus-responsive zwitterionic polymers are discussed in this discourse. The prospects shown by zwitterionic architecture suggest the tremendous potential for them in this domain. This critical review will encourage the researchers working in this area and boost the development and commercialization of such devices to benefit the healthcare fraternity.     

The dynamic interactions between the stroma,pancreatic stellate cells and pancreatic tumor development: Novel therapeutic targets

The stroma is a main driver of metastasis and aggressiveness in pancreatic cancer (PC), one of the deadliest malignancies worldwide. Pancreatic stellate cells (PSCs) form approximately 50% of the pancreatic tumor stroma, causing desmoplasia, extracellular matrix (ECM) deposition, epithelial-to-mesenchymal transition (EMT) and metastatic spread. Furthermore, activated PSCs can remodel the pancreatic tumor microenvironment (TME) via dynamic and complex interactions and feedback loops with PC cells, thus facilitating tumor growth through various signalling and immune pathways. Hence, increased understanding of these cellular cross-talks and how they shape the TME in PC might guide the development of novel treatment approaches against this stubborn and deadly malignancy that has so far resisted therapeutic advances. In this review, we will explore the role of the stroma and PSCs in PC development, invasion and metastasis, examine their interaction with PC cells and discuss potential treatment approaches aimed at targeting PSCs in order to reprogram the pancreatic tumor environment.     

微针技术用于非经皮途径的药物递送研究进展

近年来,微针作为一种新兴的经皮给药技术,具有微创、无痛、使用方便和高效的特点,逐渐成为一种极具研究价值和应用潜力的给药策略。微针技术在过去20年中得到迅速发展并呈现出多样化的趋势,已可根据不同需求来定制微针的形状、组成、机械性能和其他特殊功能等。由于微针能以微创方式穿越各种生物屏障,因此许多研究人员探索了微针在除皮肤外各类组织和器官中的药物递送应用。本文综述了微针技术及其近年来在眼睛、血管、心脏等组织和器官的药物递送中的应用研究,以期推动微针技术的应用发展。