Liposomes and their applications in molecular imaging

Molecular imaging is a relatively new discipline with a crucial role in diagnosis and treatment tracing of diseases through characterization and quantification of biological processes at cellular and sub-cellular levels of living organisms. These molecular targeted systems can be conjugated with contrast agents or radioligands to obtain specific molecular probes for the purpose of diagnosis of diseases more accurately by different imaging modalities. Nowadays, an interesting new approach to molecular imaging is the use of stealth nanosized drug delivery systems such as liposomes having convenient properties such as biodegradability, biocompatibility and non-toxicity and they can specifically be targeted to desired disease tissues by combining with specific targeting ligands and probes. The targeted liposomes as molecular probes in molecular imaging have been evaluated in this review. Therefore, the essential point is detection of molecular target of the disease which is different from normal conditions such as increase or decrease of a receptor, transporter, hormone, enzyme etc, or formation of a novel target. Transport of the diagnostic probe specifically to targeted cellular, sub-cellular or even to molecular entities can be performed by molecular imaging probes. This may lead to produce personalized medicine for imaging and/or therapy of diseases at earlier stages.     

Liposomes and their applications in molecular imaging

Molecular imaging is a relatively new discipline with a crucial role in diagnosis and treatment tracing of diseases through characterization and quantification of biological processes at cellular and sub-cellular levels of living organisms. These molecular targeted systems can be conjugated with contrast agents or radioligands to obtain specific molecular probes for the purpose of diagnosis of diseases more accurately by different imaging modalities. Nowadays, an interesting new approach to molecular imaging is the use of stealth nanosized drug delivery systems such as liposomes having convenient properties such as biodegradability, biocompatibility and non-toxicity and they can specifically be targeted to desired disease tissues by combining with specific targeting ligands and probes. The targeted liposomes as molecular probes in molecular imaging have been evaluated in this review. Therefore, the essential point is detection of molecular target of the disease which is different from normal conditions such as increase or decrease of a receptor, transporter, hormone, enzyme etc, or formation of a novel target. Transport of the diagnostic probe specifically to targeted cellular, sub-cellular or even to molecular entities can be performed by molecular imaging probes. This may lead to produce personalized medicine for imaging and/or therapy of diseases at earlier stages.     

Radionuclide imaging of drug delivery for patient selection in targeted therapy

Introduction: During the last decade, numerous antibodies and tyrosine kinase inhibitors have been developed for cancer treatment. However, only a limited number of these agents have been shown to significantly improve survival of patients. Therefore, it is of crucial importance to identify the subset of patients who benefit from targeted therapy. Biomarkers can play an important role in selecting the right drug for the right patient.

Areas covered: In this review, the potential role of molecular imaging of drug delivery for patient selection in targeted therapy will be discussed. The advantages and limitations of molecular imaging will be compared to those of conventional biomarkers. Moreover, we will address the factors that affect imaging of drug delivery, such as target expression, type of drug, in vivo accessibility of the receptor (e.g., vascular density, vascular permeability, interstitial pressure), enhanced permeability and retention (EPR) effect, receptor internalization, tracer protein dose and timing of imaging.

Expert opinion: Molecular imaging of drug delivery clearly has potential for patient selection for targeted therapy. The main advantage of this technique is that not only can antigen expression be measured noninvasively but also target accessibility is taken into account. However, up to now, most of these studies have been performed in preclinical models. Therefore, future research should focus on bringing promising tracers to the clinic, preferable in an early stage of drug development in order to test their potential role as a biomarker.     

Physiologically-based pharmacokinetic models: approaches for enabling personalized medicine

Personalized medicine strives to deliver the ‘right drug at the right dose’ by considering inter-person variability, one of the causes for therapeutic failure in specialized populations of patients. Physiologically-based pharmacokinetic (PBPK) modeling is a key tool in the advancement of personalized medicine to evaluate complex clinical scenarios, making use of physiological information as well as physicochemical data to simulate various physiological states to predict the distribution of pharmacokinetic responses. The increased dependency on PBPK models to address regulatory questions is aligned with the ability of PBPK models to minimize ethical and technical difficulties associated with pharmacokinetic and toxicology experiments for special patient populations. Subpopulation modeling can be achieved through an iterative and integrative approach using an adopt, adapt, develop, assess, amend, and deliver methodology. PBPK modeling has two valuable applications in personalized medicine: (1) determining the importance of certain subpopulations within a distribution of pharmacokinetic responses for a given drug formulation and (2) establishing the formulation design space needed to attain a targeted drug plasma concentration profile. This review article focuses on model development for physiological differences associated with sex (male vs. female), age (pediatric vs. young adults vs. elderly), disease state (healthy vs. unhealthy), and temporal variation (influence of biological rhythms), connecting them to drug product formulation development within the quality by design framework. Although PBPK modeling has come a long way, there is still a lengthy road before it can be fully accepted by pharmacologists, clinicians, and the broader industry.     

Polymeric radiotracers in nuclear imaging

Water-soluble polymers have been used in the last two decades to modify the pharmacokinetics and physicochemical properties of targeted therapeutic agents. Non-invasive imaging techniques such as nuclear imaging can be used to assess the drug delivery efficiency of novel formulations in a cost-effective fashion and thereby facilitate their development process. Polymeric radiopharmaceuticals have also been investigated on their own right as potential nuclear imaging agents. Clinical applications of polymeric radiopharmaceuticals include blood-pool imaging and targeted molecular imaging. In the latter case, water-soluble polymers are often used to modify the pharmacokinetics and biodistribution pattern of ligands that target receptors or antigens at disease sites. As advances are continue to be made in the emerging field of molecular imaging, nuclear imaging will play an increasingly important role in the development of polymeric drug delivery systems. Similarly, polymer technology will also be integrated into the development of molecularly targeted radiopharmaceuticals. Here, we review various aspects of polymeric radiotracers and their applications in nuclear imaging.     

Positron emission tomography molecular imaging for drug development

Human in vivo molecular imaging with positron emission tomography (PET) enables a new kind of 'precision pharmacology', able to address questions central to drug development. Biodistribution studies with drug molecules carrying positron-emitting radioisotopes can test whether a new chemical entity reaches a target tissue compartment (such as the brain) in sufficient amounts to be pharmacologically active. Competition studies, using a radioligand that binds to the target of therapeutic interest with adequate specificity, enable direct assessment of the relationship between drug plasma concentration and target occupancy. Tailored radiotracers can be used to measure relative rates of biological processes, while radioligands specific for tissue markers expected to change with treatment can provide specific pharmacodynamic information. Integrated application of PET and magnetic resonance imaging (MRI) methods allows molecular interactions to be related directly to anatomical or physiological changes in a tissue. Applications of imaging in early drug development can suggest approaches to patient stratification for a personalized medicine able to deliver higher value from a drug after approval. Although imaging experimental medicine adds complexity to early drug development and costs per patient are high, appropriate use can increase returns on R and D investment by improving early decision making to reduce new drug attrition in later stages. We urge that the potential value of a translational molecular imaging strategy be considered routinely and at the earliest stages of new drug development.     

Safe and effective medicines for all: is personalized medicine the answer?

An improvement in drug treatment and clinical outcome is one of the major challenges in clinical medicine. The development of evidence-based standards of care has led to a significant improvement, but, by definition, strictly standardized cohorts in clinical trials have to ignore individual differences. Personalized medicine is defined as the application of genomic and molecular data to better target the delivery of healthcare, facilitate the discovery and clinical testing of new products, and help determine a person's predisposition to a particular disease or condition. After the deciphering of the human genome, however, the high expectations in individualized medicine were not always fulfilled. However, personalized medicine has become indispensable in the treatment of malignant diseases and there is increasing evidence for its benefit in other areas. This article outlines the impact of pharmacogenetics and pharmacogenomics, especially with regard to personalized medicine, in major medical indications and reflects the obstacles and chances taken in current daily practice.     

基于分子理化性质特征的小样本G蛋白偶联受体靶点结合活性预测的深度学习模型

目的 制备一种人参皂苷Rk1修饰的伊曲康唑新型脂质体(R-ITZ-Lip)用于肿瘤治疗,并初步考察其体内外抗肿瘤药效。方法 采用逆向蒸发法制备R-ITZ-Lip,对其进行粒径、电位、包封率等表征研究；采用荧光显微镜和流式实验定性定量考察R-ITZ-Lip体外肿瘤细胞靶向性,采用活体和离体成像实验考察其体内肿瘤靶向性；采用MTT实验和肿瘤生长曲线考察其体内外药效。结果 R-ITZ-Lip外观呈圆形,平均粒径为(124.67±2.05)nm,包封率为(97.49±1.93)%；体外细胞摄取实验结果表明,R-ITZ-Lip能够被乳腺癌细胞4T1特异性摄取,活体和离体成像结果表明R-ITZ-Lip在4T1异种移植小鼠模型的肿瘤部位分布显著增强；MTT实验表明R-ITZ-Lip对4T1细胞表现出较好的抑制作用,IC50为1.37μg/ml,低于伊曲康唑胆固醇脂质体(C-ITZ-lip)的3.12μg/ml,4T1异种移植小鼠模型体内药效结果表明,R-ITZ-Lip有效地抑制了肿瘤的生长,R-ITZ-lip组的抑瘤率为83.54%,优于C-ITZ-lip组(73.87%)和ITZ注射液组(57.86%)。结论 构建了一种人参皂苷Rk1修饰的伊曲康唑新型脂质体,具有改善的制剂学性质,能够实现肿瘤的精准靶向,提高治疗效果。     

Personalized medicine: is it a pharmacogenetic mirage?

The notion of personalized medicine has developed from the application of the discipline of pharmacogenetics to clinical medicine. Although the clinical relevance of genetically-determined inter-individual differences in pharmacokinetics is poorly understood, and the genotype-phenotype association data on clinical outcomes often inconsistent, officially approved drug labels frequently include pharmacogenetic information concerning the safety and/or efficacy of a number of drugs and refer to the availability of the pharmacogenetic test concerned. Regulatory authorities differ in their approach to these issues. Evidence emerging subsequently has generally revealed the pharmacogenetic information included in the label to be premature. Revised drugs labels, together with a flurry of other collateral activities, have raised public expectations of personalized medicine, promoted as 'the right drug at the right dose the first time.' These expectations place the prescribing physician in a dilemma and at risk of litigation, especially when evidence-based information on genotype-related dosing schedules is to all intent and purposes non-existent and guidelines, intended to improve the clinical utility of available pharmacogenetic information or tests, distance themselves from any responsibility. Lack of efficacy or an adverse drug reaction is frequently related to non-genetic factors. Phenoconversion, arising from drug interactions, poses another often neglected challenge to any potential success of personalized medicine by mimicking genetically-determined enzyme deficiency. A more realistic promotion of personalized medicine should acknowledge current limitations and emphasize that pharmacogenetic testing can only improve the likelihood of diminishing a specific toxic effect or increasing the likelihood of a beneficial effect and that application of pharmacogenetics to clinical medicine cannot adequately predict drug response in individual patients.     

Biomarker World Congress 2005

This report covers some of the many excellent talks, and a selected number of posters, that were presented at this conference. It includes several emerging issues in biomarker development and the question of how biomarker science can drive targeted drug discovery and development and form a scientific basis for personalized medicine. Although relatively small, the meeting provided a good opportunity for business networking, particularly for those involved in the development and regulation of medical diagnostics and biopharmaceuticals.     

A new approach to pharmacogenomics

The medicine in the 21st century will be so called "evidence based medicine" or "personalized medicine," based on the principle of "right drug to right patient." Pharmacogenomics covers the entire spectrum of genes that determines drug behavior and sensitivity, and we anticipate it will bring major impact on the healthcare system as well as the drug discovery process in the near future. Three waves of genomic impact are predicted to arise as follows: The first wave will hit on existing drugs and late-phase development candidates within the next 2-3 years, aiming to minimize the risks in clinical trials (adverse events, resistance, etc.). The wave will then affect the candidate selection process in the early pre-development stage, and finally the disease gene finding to target discovery process. The driving force will be technologies such as SNPs database, differential gene expression (DGE) analysis, proteomics, serial analysis of gene expression (SAGE) and bioinformatics. This new approach of genomic discovery (so called "integrated approach") requires knowledge on how to implement and integrate new valuable technologies from an early stage of the discovery process. The implication of SNPs, high throughput proteomics and application of structural genomics will be the key issues in the pharmacogenomics era.     

Applications of molecular imaging in drug discovery and development process

The process of drug discovery and development requires enormous resources and time, with increasing cost for new drug development. Molecular imaging techniques have tremendous potential for improving the efficiency of drug screening, assessing the pharmacokinetics of new drugs, and evaluating drug effects. Appropriate application of molecular imaging to drug discovery and development can markedly reduce costs and the time required for new drug development. This review focuses on the contributions of molecular imaging for drug discovery and development, particularly drug screening, pharmacokinetic, preclinical and clinical drug evaluation, and for personalized and lesionalized medicine.     

Application of traditional Chinese medicine preparation in targeting drug delivery system

Abstract

Targeting drug system (TDS) or targeted drug delivery system (TDDS) is a new kind of drug delivery system which could make drug to be directly concentrated on the target site with high curative effects and low side-effects. As the quintessence of Chinese culture, traditional Chinese medicine (TCM) has a large advantage in many disease clinical treatments, especially in cancer, hypertension and many other intractable diseases owing to their low toxicity and side-effects relative to western medicine. This article reviews literatures on development of TCM-targeted preparations which were published in the past 10 years. TDS including active-targeting, passive-targeting and physical-chemical-targeting preparations were introduced through domestic and overseas literatures to reveal the unique advantages of TCM-targeting preparations in drug delivery system. In this article, we have reviewed some kinds of TCM-targeting preparations and indicated that great attention should be paid to the research on the TCM-targeting preparations.     

Functional imaging in drug discovery and development

The use of in vivo imaging with radioisotope- and magnetic resonance-based methods is increasing for all stages of drug development. The primary role for these methods has, and continues to be, clinical diagnosis, although the technology itself is highly versatile and can be adapted to very different applications. Techniques may be developed to measure the drug target, tissue-specific drug disposition and action, and to pursue basic investigations of the pathophysiology of disease. The sensitivity, spatial resolution, temporal resolution and frequency of measurement with radioisotope and magnetic resonance imaging are significantly different. Whether the application is related to the drug target, action or disease response, must first be considered before selecting which functional imaging approach can be used.     

Pharmacogenomics of human ABC transporters: detection of clinically important SNPs by SmartAmp2 method

Genetic polymorphisms and mutations in drug metabolizing enzymes, transporters, receptors, and other drug targets (e.g., toxicity targets) are linked to inter-individual differences in the efficacy and toxicity of many medications as well as risk of genetic diseases. Validation of clinically important genetic polymorphisms and the development of new technologies to rapidly detect clinically important variants are critical issues for advancing personalized medicine. A key requirement for the advancing personalized medicine resides in the ability of rapidly and conveniently testing patients' genetic polymorphisms and/or mutations. We have recently developed a rapid and cost-effective method, named Smart Amplification Process 2 (SmartAmp2), which enables us to detect genetic polymorphisms or mutations in target genes within 30 to 45 min under isothermal conditions without DNA isolation and PCR amplification. Detection of mutations or single nucleotide polymorphisms (SNPs) in human ABC transporter genes is becoming more important, since their functional impairments are reportedly associated with inherited diseases. Thus, certain genetic polymorphisms of ABC transporters are considered important biomarkers for diagnosis of inherited diseases and/or risk of drug-induced adverse reactions. In this review article, we will present the new technology of the SmartAmp2 method and its clinical applications for detection of SNPs in human ABC transporter genes, i.e., ABCC4 and ABCC11.     

Nanotechnology as a Delivery Tool for Precision Cancer Therapies

Genomic analyses from patients with cancer have improved the understanding of the genetic elements that drive the disease, provided new targets for treating this relentless disease, and offered criteria for stratifying patient populations that will benefit most from treatments. In the last decade, several new targeted therapies have been approved by the FDA based on these omics findings, leading to significantly improved survival and quality of life for select patient populations. However, many of these precision medicines, e.g., nucleic acid-based therapies and antibodies, suffer from poor plasma stability, suboptimal pharmacokinetic properties, and immunological toxicities that prohibit their clinical translation. Nanotechnology is being explored as a delivery platform that can enable the successful delivery of these precision medicine treatments without these limitations. These precision nanomedicines are able to protect the cargo from degradation or premature/burst release prior to accumulation at the tumor site and improve the selectivity to cancer cells by incorporating ligands that can target receptors overexpressed on the cancer cell surface. Here, we review the development of several precision nanomedicines based on genomic analysis of clinical samples, actively targeted nanoparticle delivery systems in the clinic, and the pathophysiological barriers of the tumor microenvironment. Successful translation of these precision nanomedicine initiatives will require an effective collaboration between basic and clinical investigators to match the right patient with the right therapies and to deliver them at therapeutic concentrations which will improve overall treatment responses.     

Impact of genetic diagnostics on drug development strategy

Innovation in diagnostics will be essential for the successful adoption of personalized medicine and will also have a major impact on the success of drug development strategies. To remain competitive, companies will need to embrace the rapid innovation in the diagnostic market, utilize diagnostic tools concurrently with research and development, and re-invent how new drugs are brought to market. In this article, specific examples of targeted oncology drugs are used to illustrate the general impact of genetic diagnostics on drug development.     

Some applications of pharmacogenomics and epigenetics in drug development and use in pursuit of personalized medicine

Personalized medicine has become the most recent mantra of the pharmaceutical industry. While truly affordable bespoke drugs may never be totally achievable, pharmacogenomics and epigenetics will play significant roles in developing targeted therapy tailored to subpopulations of disease sufferers most likely to benefit. Personalized medicine is a very attractive concept, but an extremely difficult reality to achieve due to theoretical and practical considerations. Foremost among the theoretical reasons is our dearth of knowledge of individual physiology and metabolism, as well as the interactions of genetics and environment in the development of most diseases. Amongst the practical reasons, there is the cost of new drug development, considered to be about 800 million to one billion dollars (J Health Econ 22:151-185, DiMasi et al. 2003; Health Econ 19:130-141, Adams and Vu Brantner 2010) and the fact that many drugs now on the market do display reasonable efficacy in large segments of the population with acceptable side effects. Thus, the market for "personalized" drugs may not be large enough to support the costs of development. Another factor is the limitations put on healthcare by governments and insurance companies which promote the use of generics rather than the creation of new chemical entities. Finally, there are the social and ethical considerations of turning individual biology into noughts and ones with the possibility of such information becoming public and/or being used to constrain the way one lives or the care one receives (Nat Rev Drug Discov 1:300-308, Issa 2002). That said, to the degree that personalized medicine does become possible, pharmacogenomics and epigenetics will play significant roles in drug development and use.