Multiple Therapeutic Agents Research Articles

A perspective on sympathetic renal denervation in chronic congestive heart failure.

Medical therapy has indisputably been the mainstay of management for chronic congestive heart failure. However, a significant percentage of patients continue to experience worsening heart failure (HF) symptoms despite treatment with multiple therapeutic agents. Recently, catheter-based interventional strategies that interrupt the renal sympathetic nervous system have shown promising results in providing better symptom control in patients with HF. In this article, we will review the pathophysiology of HF for better understanding of the interplay between the cardiovascular system and the kidney. Subsequently, we will briefly discuss pivotal renal denervation (RDN) therapy trials in patients with resistant hypertension and then present the available evidence on the role of RDN in HF therapy.

Enhanced cell apoptosis triggered by a multi modal mesoporous amphiphilic drug delivery system

Mesoporous magnetic nanoparticles (MMNPs) have been synthesized through a facile soft chemical route and are conjugated with multiple therapeutic agents. These MMNPs have the ability to contain and deliver both hydrophilic and hydrophobic drugs simultaneously with the mediation of an AC magnetic field (ACMF). Furthermore, the synthesis and characterization of doxorubicin hydrochloride:paclitaxel (DOX:TXL) and doxorubicin hydrochloride:cisplatin (DOX:Cis-Pt) conjugates are demonstrated. MMNPs show an excellent loading efficiency of ∼96:83% (DOX:TXL) and ∼93:83% (DOX:Cis-Pt) along with a loading capacity of ∼0.002:0.002 mg mg−1 (DOX:TXL) and ∼0.002:0.002 mg mg−1 (DOX:Cis-Pt), respectively. Over a period of 180 h, a sustained release of drugs is observed and shows a better efficiency at pH 4.3 (∼85:63%-DOX:TXL and ∼86:73%-DOX:Cis-Pt) compared to that under physiological pH conditions (∼28:22%-DOX:TXL and ∼26:22%-DOX:Cis-Pt). The MMNPs can release ∼37:22% (DOX:TXL) and ∼34:25% (DOX:Cis-Pt) within 30 min when triggered by an ACMF (at ∼43 °C). The in vitro cytotoxic effect, the ROS generation level and cell cycle distribution analysis of DOX:TXL-MMNPs and DOX:Cis-Pt-MMNPs treated MDA-MB231, MCF-7 and PC3 cancer cells are demonstrated. Enhanced cell apoptosis is observed by thermo-chemotherapy which includes application of an ACMF for 15 min. Specifically, DOX:TXL-MMNPs are more effective than DOX:Cis-Pt-MMNPs towards the PC3 cell line. The internalization of multiple drug loaded MMNPs by cells and their morphological changes due to thermo-chemotherapy are confirmed through confocal microscopy. From the present results, it is observed that the DOX:TXL and DOX:Cis-Pt conjugated MMNPs, under an ACMF, can readily minimize drug resistance. This has significantly enhanced the cell apoptosis of target cancer cells.

HYBRID INTELLIGENT CONTROLLERS FOR A MULTIPLE DRUG DELIVERY SYSTEM IN ACUTE HEART FAILURE

Regulating the dynamic responses to multiple therapeutic agents in cases of heart failure is difficult owing to time-variant changes in drug sensitivity and interaction. To address this problem, a multiple controller based on adaptive neural network (NN) predictive control has been developed for unexpected drug responses related to cardiac output and arterial pressure. However, the control speed may be slower than that in traditional controllers because of the real-time learning process for the NN. Moreover, a proportional-integral-derivative (PID) controller alone cannot automatically update the PID parameters during drug administration. This study, therefore, aimed to make hybrid intelligent (fuzzy or NN-based PID) controllers and to evaluate the control performance during multiple drug therapy in unexpected physiological responses of heart failure. The hybrid intelligent controllers were compared with the previous PID or NN controller, and they realized robust and quick control regardless of unexpected responses and acute disruptions.

Intelligent micellar polymeric nanocarriers for therapeutics and diagnosis

ABSTRACTPolymeric micelles can be designed and synthesized to bear polymeric blocks with different hydrophilicities; this triggers their self‐assembly into micellar aggregates similar to those generated with traditional surfactants. The basic structure consists of a hydrophobic core, capable of containing guest substances, and a hydrophilic shell, which stabilizes the payload and protects it from external degradation or prevents its quick elimination from the body. The accumulation of block copolymer micelles (BCMs) in a target cell or tissue can be accomplished by two main mechanisms, passive and active targeting; this allows the payload release at the site of action when desired. Hence, in this general overview, we pay special attention to newly developed single‐stimulus‐ and multi‐stimuli‐responsive delivery systems capable of disassembling and reassembling (in some cases) as a response to changes in their physicochemical properties. Also, special interest is also devoted to multifunctional BCMs incorporating multiple therapeutic agents and/or multiple imaging contrast agents, which can be considered the new generation (third generation) of drug‐delivery systems, that is, nanotheranostic platforms. Finally, a summary of BCM‐based drug‐delivery systems currently under clinical trials is given. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 42650.

Controlled release of rhEGF and rhbFGF from electrospun scaffolds for skin regeneration.

Controlled delivery of multiple therapeutic agents can be considered as an effective approach in skin tissue engineering. In this study, recombinant human epidermal growth factor (rhEGF) and recombinant human basic fibroblast growth factor (rhbFGF) encapsulated in PLGA microspheres were loaded in hybrid scaffolds of PLGA and PEO. The scaffolds with various formulations were fabricated through electrospinning in order to maintain dual, individual or different release rate of rhEGF and rhbFGF. Morphological, physical and mechanical properties of the scaffold were investigated. The scaffold possessed uniform morphology with an average diameter of 280 nm for PLGA and 760 nm for PEO nanofibers. Furthermore, the mechanical properties of the scaffolds were shown to be akin to those of human skin. Bioactivity of the scaffolds for human skin fibroblasts was evaluated. The HSF acquired significant proliferation and well-spread morphology on the scaffolds particularly in the case of different release rate of rhEGF and rhbFGF which implies the synergistic effect of the growth factors. Additionally, collagen and elastin gene expression was significantly up-regulated in the HSF seeded on the scaffolds in the case of individual delivery of rhEGF and dual delivery of rhEGF and rhbFGF. In conclusion, the prepared scaffolds as a suitable supportive substrate and multiple growth factor delivery system can find extensive utilization in skin tissue engineering.

International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators.

Estrogens are critical mediators of multiple and diverse physiologic effects throughout the body in both sexes, including the reproductive, cardiovascular, endocrine, nervous, and immune systems. As such, alterations in estrogen function play important roles in many diseases and pathophysiological conditions (including cancer), exemplified by the lower prevalence of many diseases in premenopausal women. Estrogens mediate their effects through multiple cellular receptors, including the nuclear receptor family (ERα and ERβ) and the G protein-coupled receptor (GPCR) family (GPR30/G protein-coupled estrogen receptor [GPER]). Although both receptor families can initiate rapid cell signaling and transcriptional regulation, the nuclear receptors are traditionally associated with regulating gene expression, whereas GPCRs are recognized as mediating rapid cellular signaling. Estrogen-activated pathways are not only the target of multiple therapeutic agents (e.g., tamoxifen, fulvestrant, raloxifene, and aromatase inhibitors) but are also affected by a plethora of phyto- and xeno-estrogens (e.g., genistein, coumestrol, bisphenol A, dichlorodiphenyltrichloroethane). Because of the existence of multiple estrogen receptors with overlapping ligand specificities, expression patterns, and signaling pathways, the roles of the individual receptors with respect to the diverse array of endogenous and exogenous ligands have been challenging to ascertain. The identification of GPER-selective ligands however has led to a much greater understanding of the roles of this receptor in normal physiology and disease as well as its interactions with the classic estrogen receptors ERα and ERβ and their signaling pathways. In this review, we describe the history and characterization of GPER over the past 15 years focusing on the pharmacology of steroidal and nonsteroidal compounds that have been employed to unravel the biology of this most recently recognized estrogen receptor.

Endothelin Blockade in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) remains the most common cause of chronic kidney disease and multiple therapeutic agents, primarily targeted at the renin-angiotensin system, have been assessed. Their only partial effectiveness in slowing down progression to end-stage renal disease, points out an evident need for additional effective therapies. In the context of diabetes, endothelin-1 (ET-1) has been implicated in vasoconstriction, renal injury, mesangial proliferation, glomerulosclerosis, fibrosis and inflammation, largely through activation of its endothelin A (ETA) receptor. Therefore, endothelin receptor antagonists have been proposed as potential drug targets. In experimental models of DKD, endothelin receptor antagonists have been described to improve renal injury and fibrosis, whereas clinical trials in DKD patients have shown an antiproteinuric effect. Currently, its renoprotective effect in a long-time clinical trial is being tested. This review focuses on the localization of endothelin receptors (ETA and ETB) within the kidney, as well as the ET-1 functions through them. In addition, we summarize the therapeutic benefit of endothelin receptor antagonists in experimental and human studies and the adverse effects that have been described.

Drug metabolism and drug interactions: potential application to antituberculosis drugs.

Drug-drug interaction is an important element of modern drug development. In the case of antituberculosis drugs, which are frequently administered as combinations of multiple therapeutic agents, the potential for interactions between coadministered drugs and between new and existing drugs should be considered during the development of new antituberculosis drugs and combination regimens. The current understanding of drug-drug interactions involving the first-line antituberculosis drugs is reviewed in this article, along with the approaches that are used to prospectively delineate potential interactions during development of new therapies. In addition, current knowledge gaps are identified, and future directions for enhancing the understanding of drug-drug interactions that will further facilitate the development of novel antituberculosis therapies are discussed.

Nanomedicine for Combination Therapy of Cancer

Nanomedicine for Combination Therapy of Cancer

Microglial activation as a compelling target for treating acute traumatic brain injury.

Microglia and several inflammatory cytokines and neurotrophic growth factors are involved in traumatic brain injury (TBI). Tumor necrosis factor-alpha (TNF-α) can be released by microglia, astrocytes, and neurons. TNF-α has been reported to be both proneurogenic and antineurogenic, depending upon the model, method, and cell-derived region. There are two subtypes of microglia: M1 and M2. The former (or M1 subtype of non-phagocytic microglia) is able to secrete higher levels of TNF-α but lower levels of interleukin (IL)-10 (IL-10), an anti-inflammatory cytokine. Both the proinflammatory and the pro-apoptotic function can also be promoted by activation of tumor necrosis factor-receptor 1 (TNF-R1). In contrast, M2 activation produces lower levels of TNF-α but higher levels of IL-10. Pro-growth and survival pathways can be promoted by the activation of TNFR2. During the acute stage of TBI, both M1 subtype of microglia and TNF-R1 are activated to cause higher levels of TNF-α but lower levels of IL-10, which lead to suppressed neurogenesis, neuronal loss and organ dysfunction (so-called microglial activation I). In contrast, activation of both M2 subtype of microglia and TNF-R2 is able to promote neurogenesis and tissue recovery (so-called microglial activation II). The severity of TBI depends upon the net effects between microglial activation I and microglial activation II. Indeed, by using rodent models of TBI, therapeutic evaluation studies reveal that several agents or strategies attenuate contused brain volume and neurological deficits by inhibiting microglial activation I but inducing microglial activation II. For example, etanercept therapy might attenuate contused brain volume and neurological deficits by inactivating the M1 subtype and TNF-R1 to reduce the microglial activation I response, but it might promote neurogenesis and functional recovery by activating the M2 subtype and TNF-R2. Therefore, based on microglial responses I and II, we conclude that future studies should focus on multiple therapeutic agents and strategies for optimal TBI therapy.

In vivo delivery of siRNA to the brain by carbosilane dendrimer

Nanotechnology offers a new platform for therapeutic delivery of antiretrovirals to the central nervous system (CNS). Nanoformulated antiretroviral drugs offer multifunctionality, that is, the ability to package multiple diagnostic and therapeutic agents in the same nanocompose, along with the added provisions of site-directed delivery, delivery across the blood–brain-barrier (BBB), and controlled release of therapeutics.We studied the viability of dendrimers and dendriplexes in human primary astrocytes, as well as their uptake by these astrocytes. Functional validation was performed by using specific siRNA against HIV-1 Nef to interfere to HIV-1 infectivity. A high efficiency in Nef silencing, reducing HIV-1 infectivity was observed in astrocytes treated with dendriplexes compared with control or siRandom treated astrocytes. More interestingly, we studied the biodistribution of the second generation of carbosilane dendrimer loaded with FITC (2G-(SNMe3I)11-FITC) in vivo, in BALB/c mice. Dendriplexes were inoculated into BALB/c mice by the retro-orbital venous plexus, and their localization was determined after 1 and 24h post-injection. Dendriplexes were detected inside the brain by a sensitive imaging system of fluorescent imaging in vivo (IVIS Lumina), and by confocal microscopy analysis of sections of OCT-embedded tissues. The 2G-(SNMe3I)11-FITC dendrimer transported efficiently siRNA into the brain, crossing the BBB. Moreover, this dendrimer successfully delivered and transfected siRNA to HIV-infected human primary astrocytes and achieved gene silencing without causing cytotoxicity. These results highlight the potential of this nanoformulation in the treatment of neurological disorders.

Increased Mortality in Patients with Autoimmune Hemolytic Anemia after Allogeneic Hematopoietic Stem Cell Transplantation

IntroductionAutoimmune hemolytic anemia (AIHA) is the most commonly reported autoimmune complication following hematopoietic stem cell transplantation (HSCT) with incidence of 2-6%. The risk factors and pathogenesis remain poorly understood. Treatment often requires multiple therapeutic agents with variable efficacy and outcome. However no study to date has shown whether AIHA directly results in increased mortality. In order to better understand the risk factors, mortality and management of post-HSCT AIHA, we carried out a retrospective analysis of 533 allogeneic HSCTs in adult patients performed at King’s College Hospital between 2005-2011.MethodThe median follow-up period after HSCT was 31 months (range 2.9 – 100 months). The primary endpoint was the onset of AIHA, defined by positive direct agglutinin test (DAT) arising after the HSCT, with biochemical markers of hemolysis (raised serum lactate dehydrogenase (LDH), reduced haptoglobin, or spherocytes on the blood film). Hemolysis was considered significant if the drop in hemoglobin was more than 20 g/l. Cases of DAT positivity due to ABO antibodies, as well as those with history of AIHA or positive DAT prior to HSCT were excluded. Potential risk factors for development of AIHA were calculated with univariate followed by multivariate analysis comparisons of incidence of AIHA for each clinical stratum. Kaplan-Meier method was used to compare mortality caused by AIHA against overall mortality (OM), and transplant-related mortality (TRM). AIHA was modelled as a time-dependent variable when estimating mortality. All patients alive at last follow-up who did not develop AIHA were censored.ResultsWe identified 19 cases of AIHA following HSCT (overall incidence 3.6%). The median time to onset from HSCT to AIHA was 202 days. AIHA was associated with HSCT from unrelated donors (p = 0.026; Hazard Ratio = 5.28, 95% CI = 1.22 – 22.9), and concordant sex between HSCT recipients and donors (p = 0.045; Hazard Ratio = 3.52; 95% CI = 1.03 – 12.1). No significant association was observed between AIHA and the following eight factors: recipient gender; primary hematological disease; source of hematopoietic stem cells; conditioning regimen (alemtuzumab/ATG versus non-alemtuzumab/ATG, and reduced intensity versus myeloablative); HLA mismatch between donor/recipient; ABO mismatch; recipient CMV status; and concurrent chronic GvHD. AIHA patients also exhibited high frequency of simultaneous alloimmunization to Rh antigens coinciding with the onset of AIHA, which was not due to difference in transfusion rates, and not observed in the population who tested negative for DAT.Majority of AIHA patients (14/19; 72%) required multiple agents for treatment, but only 9/19 (47%) cases achieved complete resolution of AIHA (1 with intravenous immunoglobulin; 2 with prednisolone alone; 6 with rituximab in combination with other agents). The median survival from onset of AIHA was 487 days (range 26 – 1977 days). We compared the mortality of the AIHA versus non-AIHA population that survived beyond the median time of onset for AIHA (202 days). Patients with post-transplant AIHA had a higher OM (p = 0.006, Hazard Ratio = 2.37, 95% CI = 1.28 – 4.39), 1-year OM of 22% versus 10% (p = 0.04) and 1-year TRM of 18% versus 4% (p = 0.001), respectively (Figure 1). 36% (4/11 cases) of deaths were attributable to AIHA.ConclusionThe overall incidence of AIHA following allogeneic HSCT in our study was 3.6%. The risk factors associated with AIHA were receiving HSCT from unrelated donors, and matched gender between the donor/recipient, which has not been previously reported. We observed an association between allo and autoimmunization in the AIHA patients, suggesting a common immune defect underlying both phenomena. The most effective treatment was a combination regimen of rituximab with prednisolone or other immunosuppressive agents. The overall mortality rate for our AIHA patients was high at 53% (10/19 cases), with AIHA as a cause of death in 36% of deceased patients. We have shown that AIHA following HSCTs indeed leads to increased mortality with over 2 fold higher OM in the patients with AIHA. [Display omitted] DisclosuresMcLornan:Novartis: Research Funding.

Multirate delivery of multiple therapeutic agents from metal-organic frameworks

The highly porous nature of metal-organic frameworks (MOFs) offers great potential for the delivery of therapeutic agents. Here, we show that highly porous metal-organic frameworks can be used to deliver multiple therapeutic agents—a biologically active gas, an antibiotic drug molecule, and an active metal ion—simultaneously but at different rates. The possibilities offered by delivery of multiple agents with different mechanisms of action and, in particular, variable timescales may allow new therapy approaches. Here, we show that the loaded MOFs are highly active against various strains of bacteria.

Robust, Flexible, and Bioadhesive Free-Standing Films for the Co-Delivery of Antibiotics and Growth Factors

Free-standing polymer films that adhere strongly to tissue and can codeliver multiple therapeutic agents in a controlled manner are useful as medical plasters. In this study, a bilayer polymer film comprising a drug reservoir layer and a supporting layer is fabricated by spin-coating poly(lactic-co-glycolic acid) (PLGA) on top of a layer-by-layer assembled film of poly(β-amino esters) (PAE), alginate sodium (ALG), and recombinant human basic fibroblast growth factor (bFGF). Apart from bFGF, the bilayer film can also load antibiotic drug ceftriaxone sodium (CTX) by a postdiffusion process. The PLGA supporting layer facilitates the direct peeling of the bilayer film from substrate to produce a robust and flexible free-standing film with excellent adhesion onto the human skin and porcine liver. The excellent adhesion of the bilayer film originates from the ALG component in the drug reservoir layer. CTX is quickly released by easily breaking its electrostatic interaction with the drug reservoir layer, whereas the sustained release of bFGF is due to the slow degradation of PAE component in the drug reservoir layer. Wounds can be synergetically treated by fast release of CTX to effectively eradicate invasive bacteria and by sustained release of bFGF to accelerate wound healing. Our results serve as a basis for designing multifunctional free-standing films with combination therapy for biomedical applications.

Lethal drug combination: Arsenic loaded multiple drug mesoporous silica for theranostic applications

Simultaneous delivery of multiple therapeutic agents is of great importance for effective chemotherapy due of its well-known drug synergism and suppression to chemoresistance. We report a new theranostic nanoformulation to shuttle multiple chemotherapeutic agents for successfully exterminating cancer cells. This strategy is based on the fabrication of magnetite doped mesoporous silica nanoparticles (MSNs) in which both internal porous and external surface of MSN are respectively exploited to load two different kinds of cytotoxic cargoes. Notably, an exceptionally high quantity (29%) of poorly hydrophobic drug camptothecin (CPT) is loaded into the nanopores of MSNs; however, in previous reports less than 1% loading efficiency is reported. Following CPT loading in the pores of MSNs, another unconventional but FDA approved arsenic trioxide (ATO) is conjugated onto the surface of nanocomposite via exploiting the thiophilic nature of ATO. Cell inhibition performance of dual drug nanoformulation is significantly higher than single drug formulation, possibly due to additional or synergistic effect, as low as 3μg/ml of double drug nanocarrier were found effective to exterminate cancer cells. Besides drug delivery, the presence of superparamagnetic magnetite nanocrystals additionally empowers this system to be used as a contrast agent in magnetic resonance (MR) imaging for either monitoring diseased tissues or feedback of chemotherapy. We anticipate that the integration of combination therapy with nanotechnology coupled with versatile magnetic manipulation feature may prove a significant step forward toward the development of effective theranostic agents.

Treatment of PTSD and Chronic Daily Headache.

Posttraumatic stress disorder (PTSD) is often comorbid with chronic migraine (CM) and chronic tension-type headache (CTTH). Trauma-focused cognitive behavioral psychotherapies, selective serotonin reuptake inhibitors (SSRIs), and venlafaxine have demonstrated efficacy in the treatment of PTSD. Amitriptyline, topiramate, sodium valproate, and botulinum toxin A are efficacious for treatment of chronic daily headache (CDH). Treatment studies on individuals with CDH and comorbid PTSD, however, are limited. As such, multiple therapeutic agents or modes of interventions typically are necessary, such that comprehensive treatment simultaneously utilizes approaches with established efficacy for each individual condition.

Current issues in malignant pleural mesothelioma evaluation and management.

Malignant pleural mesothelioma (MPM) is an uncommon disease most often associated with occupational asbestos exposure and is steadily increasing in worldwide incidence. Patients typically present at an older age, with advanced clinical stage and other medical comorbidities, making management quite challenging. Despite great efforts, the prognosis of MPM remains poor, especially at progression after initial treatment. Macroscopic complete resection of MPM can be achieved through extrapleural pneumonectomy (EPP) or extended (ie, radical) pleurectomy (e-P/D) in selected patients and can result in prolonged survival when incorporated into a multimodality approach. Given the morbidity associated with surgical resection of MPM, optimizing identification of appropriate patients is essential. Unfortunately, most patients are not candidates for EPP or e-P/D due to advanced stage, age, and/or medical comorbidity. Pemetrexed and platinum combination chemotherapy has become the cornerstone of therapy for patients with unresectable disease because the combination is associated with improved survival and quality of life in treated patients. However, MPM eventually becomes resistant to initial therapy, and benefit to further lines of therapy has not been substantiated in randomized clinical trials. Translational research has provided exciting insights into tumorigenesis, biomarkers, and immune response in MPM, leading to the development of multiple novel therapeutic agents that are currently in clinical trials. These advances hold the promise of a new era in the treatment of MPM and suggest that this disease will not be left behind in the war on cancer.

Tailored sequential drug release from bilayered calcium sulfate composites

The current standard for treating infected bony defects, such as those caused by periodontal disease, requires multiple time-consuming steps and often multiple procedures to fight the infection and recover lost tissue. Releasing an antibiotic followed by an osteogenic agent from a synthetic bone graft substitute could allow for a streamlined treatment, reducing the need for multiple surgeries and thereby shortening recovery time. Tailorable bilayered calcium sulfate (CS) bone graft substitutes were developed with the ability to sequentially release multiple therapeutic agents. Bilayered composite samples having a shell and core geometry were fabricated with varying amounts (1 or 10wt.%) of metronidazole-loaded poly(lactic-co-glycolic acid) (PLGA) particles embedded in the shell and simvastatin directly loaded into either the shell, core, or both. Microcomputed tomography showed the overall layered geometry as well as the uniform distribution of PLGA within the shells. Dissolution studies demonstrated that the amount of PLGA particles (i.e., 1 vs. 10wt.%) had a small but significant effect on the erosion rate (3% vs. 3.4%/d). Mechanical testing determined that introducing a layered geometry had a significant effect on the compressive strength, with an average reduction of 35%, but properties were comparable to those of mandibular trabecular bone. Sustained release of simvastatin directly loaded into CS demonstrated that changing the shell to core volume ratio dictates the duration of drug release from each layer. When loaded together in the shell or in separate layers, sequential release of metronidazole and simvastatin was achieved. By introducing a tunable, layered geometry capable of releasing multiple drugs, CS-based bone graft substitutes could be tailored in order to help streamline the multiple steps needed to regenerate tissue in infected defects.

A convergent synthetic platform for single-nanoparticle combination cancer therapy: ratiometric loading and controlled release of cisplatin, doxorubicin, and camptothecin.

The synthesis of polymer therapeutics capable of controlled loading and synchronized release of multiple therapeutic agents remains a formidable challenge in drug delivery and synthetic polymer chemistry. Herein, we report the synthesis of polymer nanoparticles (NPs) that carry precise molar ratios of doxorubicin, camptothecin, and cisplatin. To our knowledge, this work provides the first example of orthogonally triggered release of three drugs from single NPs. The highly convergent synthetic approach opens the door to new NP-based combination therapies for cancer.

Nanotechnology for Cancer Diagnostics and Therapy – An Update on Novel Molecular Players

Nanotechnology has emerged as a disruptive technology that may provide researchers with new and innova- tive ways to diagnose, treat and monitor cancer. In fact, nanomedicine approaches have delivered several strategies, such as new imaging agents, real-time assessments of therapeutic and surgical efficacy, multifunctional, targeted devices capa- ble of bypassing biological barriers to target and silence specific pathways in tumours. Of particular interest, has been the increased capability to deliver multiple therapeutic agents directly to bulk cancer cells and cancer stem cells that play a critical role in cancer growth and metastasis. These multifunctional targeted nanoconjugates are also capable of avoiding cancer resistance and monitor predictive molecular changes that open the path for preventive action against pre-cancerous cells, minimizing costs and incidence of relapses. A myriad of nanoconjugates with effective silencing and site-targeting moieties can be developed by incorporating a diverse selection of targeting, diagnostic, and therapeutic components. A discussion of the integrative effort of nanotechnology systems with recent developments of biomolecular interactions in cancer progression is clearly required. Here, we will update the state of the art related to the development and applications of nanoscale platforms and novel biomolecular players in cancer diagnosis, imaging and treatment.