HPMA在骨靶向药物输送方面的应用

本文简要的阐述了N-2-羟丙基-甲基丙烯酰胺聚合物(HPMA)在靶向药物输送方面的特性,并介绍了把N-2-羟丙基-甲基丙烯酰胺聚合物复合物应用在骨靶向方面的部分进展以及它们的体内体外的实验研究现状,以HPMA-D-Asp8-PGE1复合物为例介绍了N-2-羟丙基-甲基丙烯酰胺聚合物复合物的整体设计。     

Visualizing in vivo liposomal drug delivery in real-time

Liposomes have tremendous potential for efficient small molecule delivery. Previous studies, however, have been hampered by an inability to monitor their distribution and release of contents. Here, the authors demonstrate the real time monitoring of small molecule delivery using luciferin as a model. To monitor the release of luciferin in vivo, luciferin was packaged in thermosensitive liposomes and delivered into transgenic mice that constitutively express luciferase. Their experiments show the thermally induced release of the liposomal content in real time. In addition, the model provides evidence that the thermosensitive liposomes are stable over a long period of time ( approximately 3 weeks), and still release their content upon heating. These data present a strategy to monitor liposomal drug delivery in vivo with luciferin.     

HPMA copolymers: Origins, early developments, present, and future

The overview covers the discovery of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers, initial studies on their synthesis, evaluation of biological properties, and explorations of their potential as carriers of biologically active compounds in general and anticancer drugs in particular. The focus is on the research in the authors' laboratory — the development of macromolecular therapeutics for the treatment of cancer and musculoskeletal diseases. In addition, the evaluation of HPMA (co)polymers as building blocks of modified and new biomaterials is presented: the utilization of semitelechelic poly(HPMA) and HPMA copolymers for the modification of biomaterial and protein surfaces and the design of hybrid block and graft HPMA copolymers that self-assemble into smart hydrogels. Finally, suggestions for the design of second-generation macromolecular therapeutics are portrayed.     

Overcoming the stromal barrier for targeted delivery of HPMA copolymers to pancreatic tumors

Delivery of macromolecules to pancreatic cancer is inhibited by a dense extracellular matrix composed of hyaluronic acid, smooth muscle actin and collagen fibers. Hyaluronic acid causes a high intratumoral fluidic pressure which prevents diffusion and penetration into the pancreatic tumor. This study involves the breaking down of hyaluronic acid by treating CAPAN-1 xenograft tumors in athymic nu/nu mice with targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers radiolabeled with ¹¹¹In for single photon emission computerized tomography (SPECT) imaging. Two targeting strategies were investigated including α_vβ₃ integrin and HER2 receptors. HPMA copolymers were targeted to these receptors by conjugating short peptide ligands cRGDfK and KCCYSL to the side chains of the copolymer. Results demonstrate that tumor targeting can be achieved in vivo after treatment with hyaluronidase. This approach shows promise for enhanced delivery of polymer–peptide conjugates to solid tumors.     

Fluorescence imaging: applications in drug delivery research

In the context of drug delivery it is crucial to gain knowledge of nature of the cell's internal barriers, as well as one needs to be aware of requirements for the study of spatial and temporal interactions of drug delivery vehicles with the cell. Fluorescent imaging technology can be a great innovation in the field of science as far as study of live cell imaging and dynamic events are concerned. The technique has also demonstrated the ability to integrate the anatomic, functional, and statistical data. The current review article discusses various fluorescent techniques and also elaborates the scope of fluorescent imaging in the field of drug delivery.     

HPMA copolymers for masking and retargeting of therapeutic viruses

Hydrophilic polymers are widely used already for steric stabilisation of bioactive proteins, changing their pharmacokinetics and modifying their interactions with the biological environment. Polymers may also be conjugated to biological surfaces, such as viruses, bacteria and mammalian cells, also to endow steric protection and changed properties. Reactive polymers based on N-[2-hydroxypropyl]methacrylamide have shown particular promise for surface coating of viruses, particularly adenovirus, and here we describe the important observations and innovations arising from this combination of chemical and genetic engineering. Adenovirus is a versatile agent that already finds important experimental applications as a recombinant vaccine, and also for cancer therapy, although its activity in both settings is often limited by a potent antibody-neutralising response in humans that is generally not seen in experimental animals. Coating with HPMA copolymers provides protection against neutralisation by antibodies and complement, and covalent linkage of novel ligands to the surface of the polymer can endow new infectious tropisms, mediated through different receptors, that can expand the potential applications of this versatile technology for a range of settings.     

Amphiphilic block copolymers in drug delivery: advances in formulation structure and performance

ABSTRACT

Introduction: Nanostructured delivery vehicles can address key challenges facing drug delivery, including the lipophilic nature of therapeutic compounds and their effective transport through the body. Amphiphilic block copolymers that self-assemble offer advantages compared with homopolymer-, lipid-, and protein-based delivery vehicles. Poly(ethylene oxide)-poly(propylene oxide) amphiphilic block copolymers (Poloxamers) serve well as pharmaceutical excipients because of their highly tunable association properties, low toxicity, and ability to functionalize. The formulation nanostructure underpins performance across various administration routes and diseases, but is strongly dependent on the amphiphile, drug, and environment (temperature, concentration, and types of additives), thus demanding further elucidation.

Areas covered: The phase behavior of Poloxamers in aqueous solution is presented first, to inform an overview of drug encapsulation processes. The formulation composition and preparation method are centrally important to the nanostructure obtained. Several self-assembled structures are discussed which present advantages for particular administration routes: transdermal, ophthalmic, oral, nasal, and subcutaneous. Many diseases are treatable through these routes, e.g., inflammation, diabetes, hypertension, and cancer.

Expert opinion: The exceptional ability to tune amphiphilic block copolymer nanostructure (micelles, hydrogels, lyotropic liquid crystals, etc.) renders them a powerful tool in the formulation of drug delivery systems, offering multiple processing options and physical states to accommodate diverse drugs and administration pathways.     

Advances in lymphatic imaging and drug delivery

Cancer remains the second leading cause of death after heart disease in the US. While metastasized cancers such as breast, prostate, and colon are incurable, before their distant spread, these diseases have invaded the lymphatic system as a first step in their progression. Hence, proper evaluation of the disease state of the lymphatics which drain a tumor site is crucial to staging and the formation of a treatment plan. Current lymphatic imaging modalities with visible dyes and radionucleotide tracers offer limited sensitivity and poor resolution; however, newer tools using nanocarriers, quantum dots, and magnetic resonance imaging promise to vastly improve the staging of lymphatic spread without needless biopsies. Concurrent with the improvement of lymphatic imaging agents, has been the development of drug carriers that can localize chemotherapy to the lymphatic system, thus improving the treatment of localized disease while minimizing the exposure of healthy organs to cytotoxic drugs. This review will focus on the use of various nanoparticulate and polymeric systems that have been developed for imaging and drug delivery to the lymph system, how these new devices improve upon current technologies, and where further improvement is needed.     

Nanoparticles: a boon to drug delivery, therapeutics, diagnostics and imaging

Drug delivery is an interdisciplinary and independent field of research and is gaining the attention of pharmaceutical researchers, medical doctors and industry. A safe and targeted drug delivery could improve the performance of some classic medicines already on the market, and moreover, will have implications for the development and success of new therapeutic strategies such as anticancer drug delivery, peptide and protein delivery and gene therapy. In the last decade, several drug-delivery technologies have emerged and a fascinating part of this field is the development of nanoscale drug delivery devices. Nanoparticles (NPs) have been developed as an important strategy to deliver conventional drugs, recombinant proteins, vaccines and more recently, nucleotides. NPs and other colloidal drug-delivery systems modify the kinetics, body distribution and drug release of an associated drug. This review article focuses on the potential of nanotechnology in medicine and discusses different nanoparticulate drug-delivery systems including polymeric NPs, ceramic NPs, magnetic NPs, polymeric micelles and dendrimers as well as their applications in therapeutics, diagnostics and imaging. FROM THE CLINICAL EDITOR: This comprehensive review focuses on different nanoparticulate drug-delivery systems including polymeric NPs, ceramic NPs, magnetic NPs, polymeric micelles and dendrimers as well as their applications in therapeutics, diagnostics and imaging.     

Nanodiamond-mediated drug delivery and imaging: challenges and opportunities

Introduction: The field of nanoparticle-based therapeutic systems is rapidly expanding encompassing a wide variety of practices ranging from detection to diagnosis to treatment. Recently a great potential of nanodiamond (ND) particles as a multimodal imaging/therapy platform has been demonstrated.

Areas covered: This review describes a unique set of properties of ND particles attractive for drug delivery and imaging applications and highlights the most recent ND-based multimodal imaging/therapy approaches and related biocompatibility studies. The spectrum of major advancements includes marked improvements in tumor treatment efficacy and safety based on integration of ND with doxorubicin (DOX). Recent progress of ND-mediated drug delivery in orthopedic, dental and ophthalmic applications is also discussed.

Expert opinion: ND particles possess a unique set of properties attractive for drug delivery applications, including exceptional biocompatibility, large carrier capacity and versatile surface chemistry properties, which enhance drug binding and provide sustainable drug release. Other unique attributes of NDs embrace bright stable fluorescence based on crystallographic defects. A roadmap toward a clinical translation comprises identification of ND-therapeutic compounds that display marked improvements over clinical standards with respects to efficacy, safety and cost.     

Molecular imaging in drug development

Molecular imaging can allow the non-invasive assessment of biological and biochemical processes in living subjects. Such technologies therefore have the potential to enhance our understanding of disease and drug activity during preclinical and clinical drug development, which could aid decisions to select candidates that seem most likely to be successful or to halt the development of drugs that seem likely to ultimately fail. Here, with an emphasis on oncology, we review the applications of molecular imaging in drug development, highlighting successes and identifying key challenges that need to be addressed for successful integration of molecular imaging into the drug development process.     

HPMA copolymer-anticancer drug conjugates: design, activity, and mechanism of action.

The design, synthesis and properties of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers as carriers of anticancer drugs are reviewed. Macromolecular therapeutics based on HPMA copolymers are biocompatible, preferentially accumulate in tumors, and possess a higher anticancer efficacy than low molecular weight drugs. Novel designs of HPMA copolymer carriers resulted in long-circulating conjugates and gene and oligonucleotide delivery systems. HPMA copolymer based macromolecular therapeutics were active against numerous cancer models and are in clinical trials. The data obtained indicated that macromolecular therapeutics activated different signaling pathways and possessed a different mechanism of action than free drugs. This bodes well for the success of future research aimed at identification of new intracellular molecular targets as a basis for the design of the second generation of macromolecular therapeutics.     

Imaging techniques for assessing drug delivery in man

In vivo imaging technologies have a vital role to play in the pharmaceutical development process. Gamma scintigraphy, comprising two-dimensional ‘planar' imaging, is used widely to visualize and to quantify drug delivery, particularly by the oral and pulmonary routes. However, three-dimensional imaging modalities – single photon emission computed tomography (SPECT), positron emission tomography (PET) and magnetic resonance imaging (MRI) – may also have applications within this area. Single photon emission computed tomography and PET offer potential advantages over gamma scintigraphy in the assessment of regional lung deposition from aerosol inhalers, but these advantages are greatly outweighed by the practical problems associated with conducting SPECT and PET studies. It is concluded that, for the foreseeable future, gamma scintigraphy is the imaging modality of choice in assessing the delivery of new oral and pulmonary drug products.     

Microneedle-based drug delivery systems: Microfabrication,drug delivery,and safety

Many promising therapeutic agents are limited by their inability to reach the systemic circulation, due to the excellent barrier properties of biological membranes, such as the stratum corneum (SC) of the skin or the sclera/cornea of the eye and others. The outermost layer of the skin, the SC, is the principal barrier to topically-applied medications. The intact SC thus provides the main barrier to exogenous substances, including drugs. Only drugs with very specific physicochemical properties (molecular weight < 500?Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Transdermal delivery of hydrophilic drugs and macromolecular agents of interest, including peptides, DNA, and small interfering RNA is problematic. Therefore, facilitation of drug penetration through the SC may involve by-pass or reversible disruption of SC molecular architecture. Microneedles (MNs), when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. These micropores are orders of magnitude larger than molecular dimensions, and, therefore, should readily permit the transport of hydrophilic macromolecules. Various strategies have been employed by many research groups and pharmaceutical companies worldwide, for the fabrication of MNs. This review details various types of MNs, fabrication methods and, importantly, investigations of clinical safety of MN.     

Alginate graft copolymers and alginate-co-excipient physical mixture in oral drug delivery

Objectives Use of alginate graft copolymers in oral drug delivery reduces dosage form manufacture complexity with reference to mixing or coating processes. It is deemed to give constant or approximately steady weight ratio of alginate to covalently attached co‐excipient in copolymers, thereby leading to controllable matrix processing and drug release. This review describes various grafting approaches and their outcome on oral drug release behaviour of alginate graft copolymeric matrices. It examines drug release modulation mechanism of alginate graft copolymers against that of co‐excipients in non‐grafted formulations. Key findings Drug release from alginate matrices can be modulated through using either co‐excipients or graft copolymers via changing their swelling, erosion, hydrophobicity/hydrophilicity, porosity and/or drug adsorption capacity. However, it is not known if the drug delivery performance of formulations prepared using alginate graft copolymers is superior to those incorporating graft‐equivalent co‐excipient physically in a dosage form without grafting but at the corresponding graft weight, owing to limited studies being available. Conclusions The value of alginate graft copolymers as the potential alternative to alginate–co‐excipient physical mixture in oral drug delivery cannot be entirely defined by past and present research. Such an issue is complicated by the lack of green chemistry graft copolymer synthesis approach, high grafting process cost, complications and hazards, and the formed graft copolymers having unknown toxicity. Future research will need to address these matters to achieve a widespread commercialization and industrial application of alginate graft copolymers in oral drug delivery