Nanoparticle-based combination therapy toward overcoming drug resistance in cancer

The use of multiple therapeutic agents in combination has become the primary strategy to treat drug resistant cancers. However, administration of combinatorial regimens is limited by the varying pharmacokinetics of different drugs, which results in inconsistent drug uptake and suboptimal drug combination at the tumor sites. Conventional combination strategies in aim to maximize therapeutic efficacy based on maximum tolerated dose does not account for the therapeutic synergism that is sensitive to both dosing and scheduling of multiple drugs. In the present review, we will discuss the development of multidrug-loaded nanoparticles against drug resistant cancers. Nanoparticle-based combination therapy against experimental multidrug resistant (MDR) cancer models will be summarized. In addition, we will highlight the recent advances in nanoparticle-based combination strategies against clinical cancer drug resistance, including co-encapsulation of drugs with different physicochemical properties, ratiometric control over drug loading, and temporal sequencing on drug release. These emerging strategies promise novel and better tailored combinatorial regimens for clinical cancer treatment.     

Nanoparticle-based theranostic agents

Theranostic nanomedicine is emerging as a promising therapeutic paradigm. It takes advantage of the high capacity of nanoplatforms to ferry cargo and loads onto them both imaging and therapeutic functions. The resulting nanosystems, capable of diagnosis, drug delivery and monitoring of therapeutic response, are expected to play a significant role in the dawning era of personalized medicine, and much research effort has been devoted toward that goal. A convenience in constructing such function-integrated agents is that many nanoplatforms are already, themselves, imaging agents. Their well-developed surface chemistry makes it easy to load them with pharmaceutics and promote them to be theranostic nanosystems. Iron oxide nanoparticles, quantum dots, carbon nanotubes, gold nanoparticles and silica nanoparticles, have been previously well investigated in the imaging setting and are candidate nanoplatforms for building up nanoparticle-based theranostics. In the current article, we will outline the progress along this line, organized by the category of the core materials. We will focus on construction strategies and will discuss the challenges and opportunities associated with this emerging technology.     

Nanoparticle-based microextraction techniques in bioanalysis

Nanoparticles (NPs) have attracted a great deal of attention in the last decade due to their exceptional mechanical, optical and electronic properties. This article deals with the use of NPs as probes for the extraction of biomolecules from biological samples. In this context, NPs present some advantages compared with conventional sorbents. Their high surface-to-volume ratio, easy synthetic (especially for inorganic NPs) and derivatization procedures, and their biocompatibility make them a powerful alternative. In order to provide a systematic approach to the topic, NPs have been divided into two general groups attending to their chemical nature. Carbon-based (e.g., fullerene and nanotubes) and inorganic NPs (e.g., gold and magnetic NPs) are considered in depth, explaining their main properties and applications. After these critical considerations, the most important conclusions and essential trends in this field are also outlined.     

Nanoparticle-based immunopotentiation via tetanus toxoid-loaded gelatin and aminated gelatin nanoparticles

Gelatin nanoparticles (GNPs) and aminated gelatin nanoparticles (AGNPs) were prepared and used as an adjuvant to improve the delivery of tetanus toxoid (TT). Nanoparticles were characterized in vitro for their size, shape, entrapment, and release. TT-FITC conjugate was used to determine entrapment and release from nanoparticles. The immune-stimulating activity was studied by measuring anti-TT IgG, IgG1, and IgG2a isotype and cytokine responses following subcutaneous (s.c) injection of nanoparticles in BALB/c mice and was compared with alum-TT vaccine. Gelatin and aminated gelatin (AG) specific IgG response was also determined. Both GNPs and AGNPs demonstrated comparable IgG response and a significantly higher (p?< 0.05) cytokine response (IL-2 and IFN γ) as compared to alum-TT vaccine. Nanoparticulate formulations elicited both Th1 and Th2 responses and induced negligible undesirable immunogenicity against the carrier, as demonstrated by lower level of gelatin and AG-specific IgG response as compared to control.     

Epistaxis: diagnosis and therapy

Epistaxis or nosebleed is one of the most frequent emergencies in otorhinolaryngology. It is clearly an important condition--not only to the ear-nose-throat (ENT)-specialist but also to any general practitioner. This review looks at the aetiology, associated clinical considerations and evolution of its management. Intractable epistaxis requires a broad armamentarium of different diagnostic and therapeutic options.     

Nanoparticle-based immunopotentiation via tetanus toxoid-loaded gelatin and aminated gelatin nanoparticles

Gelatin nanoparticles (GNPs) and aminated gelatin nanoparticles (AGNPs) were prepared and used as an adjuvant to improve the delivery of tetanus toxoid (TT). Nanoparticles were characterized in vitro for their size, shape, entrapment, and release. TT-FITC conjugate was used to determine entrapment and release from nanoparticles. The immune-stimulating activity was studied by measuring anti-TT IgG, IgG1, and IgG2a isotype and cytokine responses following subcutaneous (s.c) injection of nanoparticles in BALB/c mice and was compared with alum-TT vaccine. Gelatin and aminated gelatin (AG) specific IgG response was also determined. Both GNPs and AGNPs demonstrated comparable IgG response and a significantly higher (p?<?0.05) cytokine response (IL-2 and IFN γ) as compared to alum-TT vaccine. Nanoparticulate formulations elicited both Th1 and Th2 responses and induced negligible undesirable immunogenicity against the carrier, as demonstrated by lower level of gelatin and AG-specific IgG response as compared to control.     

Nanoparticle-based vaginal drug delivery systems for HIV prevention

Importance of the Field: Several strategies are being investigated for the prevention of heterosexual transmission of HIV. Of these, topical vaginal drug delivery systems, microbicides, are being actively pursued. HIV prevention by means of a topical microbicide has several drug delivery challenges. These challenges include the vaginal mucosal barriers and potential degradation of the drugs in the vaginal lumen due to pH and enzymes present. Also, new drugs being evaluated as microbicides have specific mechanisms of action, which in some cases require drug targeting to a specific site of action. Nanoparticles provide a delivery strategy for targeted or controlled delivery to the vagina which can be applied in the field of HIV prevention.

Areas covered in the review: This review summarizes nanoparticulate systems and their use in mucosal delivery to date. The sexual transmission of HIV along with the various targets to prevent transmission are discussed as well as the potential opportunities, challenges and advantages in using a nanoparticle-based approach for microbicidal drug delivery.

What the reader will gain: This review provides a general understanding of vaginal drug delivery, its challenges, and nanoparticulate delivery systems. Additionally, insight will be gained as to the limited existing application of this technology to the field of HIV prevention.

Take home message: To date, few studies have been published that exploit nanoparticle-based microbicidal delivery to the vagina. The use of nanoparticles for vaginal drug delivery provides an approach to overcome the existing barriers to success.     

Nanoparticles in cancer therapy and diagnosis

Numerous investigations have shown that both tissue and cell distribution profiles of anticancer drugs can be controlled by their entrapment in submicronic colloidal systems (nanoparticles). The rationale behind this approach is to increase antitumor efficacy, while reducing systemic side-effects. This review provides an update of tumor targeting with conventional or long-circulating nanoparticles. The in vivo fate of these systems, after intravascular or tumoral administration, is discussed, as well as the mechanism involved in tumor regression. Nanoparticles are also of benefit for the selective delivery of oligonucleotides to tumor cells. Moreover, certain types of nanoparticles showed some interesting capacity to reverse MDR resistance, which is a major problem in chemotherapy. The first experiments, aiming to decorate nanoparticles with molecular ligand for 'active' targeting of cancerous cells, are also discussed here. The last part of this review focus on the application of nanoparticles in imaging for cancer diagnosis.     

Nanoparticles in cancer therapy and diagnosis

Numerous investigations have shown that both tissue and cell distribution profiles of anticancer drugs can be controlled by their entrapment in submicronic colloidal systems (nanoparticles). The rationale behind this approach is to increase antitumor efficacy, while reducing systemic side-effects. This review provides an update of tumor targeting with conventional or long-circulating nanoparticles. The in vivo fate of these systems, after intravascular or tumoral administration, is discussed, as well as the mechanism involved in tumor regression. Nanoparticles are also of benefit for the selective delivery of oligonucleotides to tumor cells. Moreover, certain types of nanoparticles showed some interesting capacity to reverse MDR resistance, which is a major problem in chemotherapy. The first experiments, aiming to decorate nanoparticles with molecular ligand for ‘active’ targeting of cancerous cells, are also discussed here. The last part of this review focus on the application of nanoparticles in imaging for cancer diagnosis.     

Nanoparticle-based laser desorption/ionization mass spectrometric analysis of drugs and metabolites

Nanoparticle-assisted laser desorption/ionization mass spectrometry (LDI-MS) is a powerful tool for the analysis of a wide range of molecules. Many of the drawbacks in the matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) can be avoided with the application of nanomaterials as matrices as well as substrates for the LDI-MS to achieve a low background noise in low m/z region and high reproducibility. Surface-assisted LDI (SALDI)-MS, especially the nanoparticle-based LDI-MS, has emerged as a promising technique for the analysis of trace amounts of substances in various biological samples due to their high surface area for analyte enrichment, efficient desorption/ionization, and homogeneous crystallization of sample. Therefore, it is highly useful in clinical, forensic, medical, food and drug analyses, disease diagnosis, and various other fields. In this review, we briefly discuss the application of various nanomaterials, which include metal-based, carbon-based, silicon-based nanomaterials and nanocomposites, as matrices and substrates for LDI-MS based drug and metabolite analyses and possible detection strategies. Also, we discuss the idea of using “mass tag” for signal amplification for drug and metabolite detection using nanoparticle assisted LDI-MS.     

阿尔茨海默病的基因诊断和治疗

尽管阿尔茨海默病(AD)早在一个世纪前便已被人类认识,但其病因至今尚未完全阐明.人类遗传学的最新研究显示,3种基因(APP、PSEN1和PSEN2)与早发型家族性AD有关,载脂蛋白E可增加遗传性和散发性AD的风险.本文综述人类基因组研究对AD诊断及预防的影响.     

Brain cancer diagnosis and therapy with nanoplatforms

Treatment of brain cancer remains a challenge despite recent improvements in surgery and multimodal adjuvant therapy. Drug therapies of brain cancer have been particularly inefficient, due to the blood-brain barrier and the non-specificity of the potentially toxic drugs. The nanoparticle has emerged as a potential vector for brain delivery, able to overcome the problems of current strategies. Moreover, multi-functionality can be engineered into a single nanoplatform so that it can provide tumor-specific detection, treatment, and follow-up monitoring. Such multitasking is not possible with conventional technologies. This review describes recent advances in nanoparticle-based detection and therapy of brain cancer. The advantages of nanoparticle-based delivery and the types of nanoparticle systems under investigation are described, as well as their applications.     

B-type natriuretic peptide for diagnosis and therapy

Brain natriuretic peptide (BNP) plays an important role in cardiovascular homeostasis. Plasma BNP increases markedly in left ventricular dysfunction from several causes, and its levels in heart failure (HF) correlate with symptoms severity. BNP has recently emerged as a potentially important clinical marker for the diagnosis of HF in patients with unexplained dyspnea. Other clinical applications of BNP, such as screening for asymptomatic ventricular dysfunction, establishing the prognosis or guiding the titration of drug therapy, are under investigation and have not yet been sufficiently validated for widespread clinical use. Laboratory-based and point-of-care analyses are available for BNP and N-terminal proBNP as fully-automated immunoassays. Several patented inventions and reagents for the diagnosis of various heart pathologies provide helpful information, particularly in conjunction with other clinical tests. They also have prognostic value for future cardiovascular events. Patents owned by Scios Inc. recommended recombinant BNP for managing acute decompensated HF. However, this treatment apparently has safety problems and no proven clinical advantage over existing treatments in terms of improved survival and prevention of subsequent hospitalizations.     

Combinatorial nanoparticles for cancer diagnosis and therapy

Nanotechnology when engineered together with biotechnology opens a fascinating field with applications in diverse areas such as drug targeting and delivery, medical imaging, biosensing, biomaterials and nanotechnology. Conjugating nanoparticles with biomolecules like QD-herceptin conjugates or QD-aptamer (Apt)-DOX conjugates provides many opportunities for improving many of the current challenges in cancer diagnosis and therapy. This paper reviews combinatorial nanoparticles designed and formulated for cancer imaging and therapy, including inorganic nanoparticles (quantum dots, iron oxide particles, gold nanoparticles and silica and carbon nanoparticles), polymeric nanoparticles (PLGA, PLGA-PEG, PAMAM), liposomes and lipid nanoparticles. These nanoparticles are multifunctional in nature and combine two or more functions like targeting, imaging and therapy. In this review, we have classified these combinatorial targeted nanoparticles into inorganic, polymeric and liposome based nanosystems.