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。     

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.     

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。     

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.     

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.     

Doxorubicin-loaded pH-responsive chitin nanogels for drug delivery to cancer cells

This work deals with preparation of doxorubicin loaded chitin nanogels and were characterized by SEM, DLS and FTIR for cancer drug delivery. The in vitro cytotoxicity studies of 130-160 nm sized doxorubicin loaded chitin nanogels were studied using MTT assay on L929, PC3, MCF-7, A549 and HEPG2 confirmed that relatively higher toxicity on cancer cells comparing to normal L929 cells. The internalization studies showed a significant uptake of doxorubicin loaded chitin nanogels in all the tested cell lines. All the above results indicated that doxorubicin loaded chitin nanogels can be used for prostate, breast, lung and liver cancer.     

Enhanced gene delivery to HER-2-overexpressing breast cancer cells by modified immunolipoplexes conjugated with the anti-HER-2 antibody

Cationic liposome-mediated gene delivery to tumors has met with only limited success due to the low transfection efficiency and lack of target specificity. We developed a gene delivery system for HER-2-overexpressing cells by adding modified anti-HER-2 Fab' fragments to liposome/DNA complexes (lipoplexes). The modified anti-HER-2-Fab' was conjugated to liposomes containing cationic lipids such as 1,2-dioleoyl-3-(trimethylammonium) propane and cholesterol (1:1 w/w) using a maleimido-polyethyleneglycol-3400-1,2-dioleoyl-3-sn-phosphatidylethanolamine linker. The specific modification constricted the sizes of these immunolipoplexes to a range of 0.3- 0.7 microm, and they remained stable for a longer duration of time compared to the lipoplex controls (0.8-3.2 microm at 4 h). In addition, a 10-fold increase in luciferase activity was achieved after transfecting human breast cancer SK-BR3 cells with immunolipoplexes as compared to the control lipoplexes. Flow cytometry analysis demonstrated that 80% of SK-BR3 cells expressed the green fluorescent protein (GFP) 48 h after being transfected with immunolipoplexes, while only 40% of those with control lipoplexes and 3% of those with naked DNA alone expressed GFP. Furthermore, the anti-HER-2 immunolipoplexes showed specific enhancement of transfection efficiency in HER-2-overexpressing SK-BR3 cells (a 6-fold increase in luciferase activity) but not in HER-2-negative MCF-7 breast cancer cells. The enhancement of gene delivery by anti-HER-2 immunoliposomes was not affected by the presence of serum. These results demonstrate the feasibility of improving target-specific gene delivery to HER-2-overexpressing cells by insertion of lipid-modified anti-HER-2-Fab' into the preformed liposomes.     

Immunoassay-based proteome profiling of 24 pancreatic cancer cell lines

Pancreatic ductal adenocarcinoma is one of the most deadly forms of cancers, with a mortality that is almost identical to incidence. The inability to predict, detect or diagnose the disease early and its resistance to all current treatment modalities but surgery are the prime challenges to changing the devastating prognosis. Also, relatively little is known about pancreatic carcinogenesis. In order to better understand relevant aspects of pathophysiology, differentiation, and transformation, we analysed the cellular proteomes of 24 pancreatic cancer cell lines and two controls using an antibody microarray that targets 741 cancer-related proteins. In this analysis, 72 distinct disease marker proteins were identified that had not been described before. Additionally, categorizing cancer cells in accordance to their original location (primary tumour, liver metastases, or ascites) was made possible. A comparison of the cells' degree of differentiation (well, moderately, or poorly differentiated) resulted in unique marker sets of high relevance. Last, 187 proteins were differentially expressed in primary versus metastatic cancer cells, of which the majority is functionally related to cellular movement.     

Perspectives on transdermal ultrasound mediated drug delivery

The use of needles for multiple injection of drugs, such as insulin for diabetes, can be painful. As a result, prescribed drug noncompliance can result in severe medical complications. Several noninvasive methods exist for transdermal drug delivery. These include chemical mediation using liposomes and chemical enhancers or physical mechanisms such as microneedles, iontophoresis, electroporation, and ultrasound. Ultrasound enhanced transdermal drug delivery offers advantages over traditional drug delivery methods which are often invasive and painful. A broad review of the transdermal ultrasound drug delivery literature has shown that this technology offers promising potential for noninvasive drug administration. From a clinical perspective, few drugs, proteins or peptides have been successfully administered transdermally because of the low skin permeability to these relatively large molecules, although much work is underway to resolve this problem. The proposed mechanism of ultrasound has been suggested to be the result of cavitation, which is discussed along with the bioeffects from therapeutic ultrasound. For low frequencies, potential transducers which can be used for drug delivery are discussed, along with cautions regarding ultrasound safety versus efficacy.     

Therapeutic gene delivery and transfection in human pancreatic cancer cells using epidermal growth factor receptor-targeted gelatin nanoparticles

More than 32,000 patients are diagnosed with pancreatic cancer in the United States per year and the disease is associated with very high mortality (1). Urgent need exists to develop novel clinically-translatable therapeutic strategies that can improve on the dismal survival statistics of pancreatic cancer patients. Although gene therapy in cancer has shown a tremendous promise, the major challenge is in the development of safe and effective delivery system, which can lead to sustained transgene expression. Gelatin is one of the most versatile natural biopolymer, widely used in food and pharmaceutical products. Previous studies from our laboratory have shown that type B gelatin could physical encapsulate DNA, which preserved the supercoiled structure of the plasmid and improved transfection efficiency upon intracellular delivery. By thiolation of gelatin, the sulfhydryl groups could be introduced into the polymer and would form disulfide bond within nanoparticles, which stabilizes the whole complex and once disulfide bond is broken due to the presence of glutathione in cytosol, payload would be released (2-5). Poly(ethylene glycol) (PEG)-modified GENS, when administered into the systemic circulation, provides long-circulation times and preferentially targets to the tumor mass due to the hyper-permeability of the neovasculature by the enhanced permeability and retention effect (6). Studies have shown over-expression of the epidermal growth factor receptor (EGFR) on Panc-1 human pancreatic adenocarcinoma cells (7). In order to actively target pancreatic cancer cell line, EGFR specific peptide was conjugated on the particle surface through a PEG spacer.(8) Most anti-tumor gene therapies are focused on administration of the tumor suppressor genes, such as wild-type p53 (wt-p53), to restore the pro-apoptotic function in the cells (9). The p53 mechanism functions as a critical signaling pathway in cell growth, which regulates apoptosis, cell cycle arrest, metabolism and other processes (10). In pancreatic cancer, most cells have mutations in p53 protein, causing the loss of apoptotic activity. With the introduction of wt-p53, the apoptosis could be repaired and further triggers cell death in cancer cells (11). Based on the above rationale, we have designed EGFR targeting peptide-modified thiolated gelatin nanoparticles for wt-p53 gene delivery and evaluated delivery efficiency and transfection in Panc-1 cells.     

Receptor-targeted nanocarriers for therapeutic delivery to cancer

Abstract

Efficient and site-specific delivery of therapeutic drugs is a critical challenge in clinical treatment of cancer. Nano-sized carriers such as liposomes, micelles, and polymeric nanoparticles have been investigated for improving bioavailability and pharmacokinetic properties of therapeutics via various mechanisms, for example, the enhanced permeability and retention (EPR) effect. Further improvement can potentially be achieved by conjugation of targeting ligands onto nanocarriers to achieve selective delivery to the tumour cell or the tumour vasculature. Indeed, receptor-targeted nanocarrier delivery has been shown to improve therapeutic responses both in vitro and in vivo. A variety of ligands have been investigated including folate, transferrin, antibodies, peptides and aptamers. Multiple functionalities can be incorporated into the design of nanoparticles, e.g., to enable imaging and triggered intracellular drug release. In this review, we mainly focus on recent advances on the development of targeted nanocarriers and will introduce novel concepts such as multi-targeting and multi-functional nanoparticles.     

Curdlan gels as protein drug delivery vehicles

The use of curdlan, a natural -1,3-glucan, in protein drug delivery vehicles was studied by carrying out in vitro release studies with curdlan gels containing bovine serum albumin (BSA) as a model protein. Addition of urea (8 M) decreased the gel formation temperature to 37°C. Curdlan was hydroxyethylated in order to form gels under mild conditions such as physiological temperature and pH. In gels formed in 8 M urea solution, urea was almost released after 2 h while BSA was completely released after 45–100 h. The total time for complete release of BSA increased with curdlan concentration within gels. The strength of hydroxyethylated curdlan gels (385.7 dyne cm^–2) was weaker than that of curdlan gels formed in 8 M urea solution (6277 dyne cm^–2).     

Clostridial neurotoxins as a drug delivery vehicle targeting nervous system

Several neuronal disorders require drug treatment using drug delivery systems for specific delivery of the drugs for the targeted tissues, both at the peripheral and central nervous system levels. We describe a review of information currently available on the potential use of appropriate domains of clostridial neurotoxins, tetanus and botulinum, for effective drug delivery to neuronal systems. While both tetanus and botulinum neurotoxins are capable of delivering drugs the neuronal cells, tetanus neurotoxin is limited in clinical use because of general immunization of population against tetanus. Botulinum neurotoxin which is also being used as a therapeutic reagent has strong potential for drug delivery to nervous tissues.     

Long-term biocompatibility of NanoGATE drug delivery implant

The fouling of components and the formation of a fibrotic tissue capsule around subcutaneously implanted medical devices are two major obstacles in developing viable, long-term implantable drug delivery systems. NanoGATE is a subcutaneous implant designed for constant-output passive diffusion of a drug of interest through a silicon nanopore membrane. To this end, we have investigated the long-term in vivo biocompatibility of the NanoGATE implant in terms of the fouling of the nanopore membrane and the formation of a fibrotic tissue capsule around the implant. We have also evaluated how these effects influence diffusion of a lysozyme surrogate from the device once implanted within the vascular compartment of a Sprague-Dawley rat model. Using several model biomolecules such as glucose, lysozyme, and albumin, our studies suggest that silicon nanopore membranes do not foul when implanted subcutaneously for 6 mo. This study also reveals the tissue capsule that naturally forms around the implant does not limit diffusion of molecules with molecular weights on the order of 14.4 kDa at therapeutic delivery rates of tens of micrograms per day. This indicates that our NanoGATE implant should be completely functional in vivo, providing constant release levels of a drug over an extended time period. Thus, by adjusting the release rate to fit the pharmacokinetic clearance profile of the Sprague-Dawley rat, long-term steady-state blood plasma concentrations can be achieved.     

Synthesis and biological evaluation of Doxorubicin-containing conjugate targeting PSMA

Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), has recently emerged as a prominent biomarker of prostate cancer (PC) and as an attractive protein trap for drug targeting. At the present time, several drugs and molecular diagnostic tools conjugated with selective PSMA ligands are actively evaluated in different preclinical and clinical trials. In the current work, we discuss design, synthesis and a preliminary biological evaluation of PSMA-specific small-molecule carrier equipped by Doxorubicin (Dox). We have introduced an unstable azo-linker between Dox and the carrier hence the designed compound does release the active substance inside cancer cells thereby providing a relatively high Dox concentration in nuclei and a relevant cytotoxic effect. In contrast, we have also synthesized a similar conjugate with a stable amide linker and it did not release the drug at all. This compound was predominantly accumulated in cytoplasm and did not cause cell death. Preliminary in vivo evaluation has showed good efficiency for the degradable conjugate against PC3-PIP(PSMA⁺)-containing xenograft mine. Thus, we have demonstrated that the conjugate can be used as a template to design novel analogues with improved targeting, anticancer activity and lower rate of potential side effects. 3D molecular docking study has also been performed to elucidate the underlying mechanism of binding and to further optimization of the linker area for improving the target affinity.