Chimeric Drug Research Articles

Bio-inspired chimeric drug delivery nano systems (Chi-DDnSs): their fractal hologram and regulatory aspects.

Pharmaceutical Nanotechnology can provide challenges for producing innovative drugs based on bio-inspired nanostructures (advanced Drug Delivery nano Systems—aDDnSs) [1]. These systems could be correlated to the living organisms due to their self-assembly properties, their hierarchical structural organization, as well as to their biocompatibility and biodegradability characteristics. aDDnSs can be considered as new therapeutic outcomes in nanomedicine that may be able to deliver pharmacomolecules to specific tissues and can improve their PK/PD (pharmacokinetics/pharmacodynamics) behavior and affect their total bioavailability. Drug delivery is a scientific sector that promotes the innovation by designing formulation approaches that can produce aDDnSs. Drug nanocarriers produced by the combination of bionanomaterials, such as liposomes, (co)polymers and dendrimers, are considered as new classes of complex self-assembled soft nanostructures.

ChemInform Abstract: Multifunctional Compounds: Smart Molecules for Multifactorial Diseases

AbstractReview: 112 refs.

The imaging and the fractal metrology of chimeric liposomal Drug Delivery nano Systems: the role of macromolecular architecture of polymeric guest

The major advance of mixed liposomes (the so-called chimeric systems) is to control the size, structure, and morphology of these nanoassemblies, and therefore, system colloidal properties, with the aid of a large variety of parameters, such as chemical architecture and composition. The goal of this study is to investigate the alterations of the physicochemical and morphological characteristics of chimeric dipalmitoylphosphatidylcholine (DPPC) liposomes, caused by the incorporation of block and gradient copolymers (different macromolecular architecture) with different chemical compositions (different amounts of hydrophobic component). Light scattering techniques were utilized in order to characterize physicochemically and to delineate the fractal morphology of chimeric liposomes. In this study, we also investigated the structural differences between the prepared chimeric liposomes as are visualized by scanning electron microscopy (SEM). It could be concluded that all the chimeric liposomes have regular structure, as SEM images revealed, while their fractal dimensionality was found to be dependent on the macromolecular architecture of the polymeric guest.

Multifunctional compounds: Smart molecules for multifactorial diseases

Multifunctional compounds (MFCs) are designed broadly as hybrid or conjugated drugs or as chimeric drugs from two or more pharmacophores/drugs having specific pharmacological activities. These are capable of eliciting multiple pharmacological actions and have emerged as magic bullets in treatment of multifactorial diseases. Many research articles disclosing the development of such compounds for treatment of multifactorial diseases are published during last 7 years. Some successful MFC candidates for multifactorial CNS disorders include ziprasidone, duloxetine, ladostigil and M-30 whereas sunitinib, lapatinib and synthetic oleandane triterpinoids are the successful MFC candidates for various cancers. Many more compounds derived from berberine, tacrine, artemisnin, quinine, NSAIDs, pralidoxine, donepezil, rivastigmine, curcumin and various antioxidants are under investigations for exploration of their multifunctional potential. In general, MFCs possess the advantages of reduced molecularity, no drug–drug interactions and improved pharmacokinetics and pharmacodynamics. A MFC derived from two or more different pharmacophores exerts its activities by interacting with respective receptors of its constituent pharmacophores. It may also exhibit additional binding interactions with the receptor sites that may be responsible for significantly improved or additional activities. The present review discusses various MFCs developed for specific class of disorders with an aim to provide an insight into the strategies in medicinal chemistry for development of such compounds.

Synergistic gene and drug tumor therapy using a chimeric peptide

Co-delivery of gene and drug for synergistic therapy has provided a promising strategy to cure devastating diseases. Here, an amphiphilic chimeric peptide (Fmoc)2KH7-TAT with pH-responsibility for gene and drug delivery was designed and fabricated. As a drug carrier, the micelles self-assembled from the peptide exhibited a much faster doxorubicin (DOX) release rate at pH 5.0 than that at pH 7.4. As a non-viral gene vector, (Fmoc)2KH7-TAT peptide could satisfactorily mediate transfection of pGL-3 reporter plasmid with or without the existence of serum in both 293T and HeLa cell-lines. Besides, the endosome escape capability of peptide/DNA complexes was investigated by confocal laser scanning microscopy (CLSM). To evaluate the co-delivery efficiency and the synergistic anti-tumor effect of gene and drug, p53 plasmid and DOX were simultaneously loaded in the peptide micelles to form micelleplexes during the self-assembly of the peptide. Cellular uptake and intracellular delivery of gene and drug were studied by CLSM and flow cytometry respectively. And p53 protein expression was determined via Western blot analysis. The in vitro cytotoxicity and in vivo tumor inhibition effect were also studied. Results suggest that the co-delivery of gene and drug from peptide micelles resulted in effective cell growth inhibition in vitro and significant tumor growth restraining in vivo. The chimeric peptide-based gene and drug co-delivery system will find great potential for tumor therapy.

A Mathematical Model for the Rational Design of Chimeric Ligands in Selective Drug Therapies

Chimeric drugs with selective potential toward specific cell types constitute one of the most promising forefronts of modern Pharmacology. We present a mathematical model to test and optimize these synthetic constructs, as an alternative to conventional empirical design. We take as a case study a chimeric construct composed of epidermal growth factor (EGF) linked to different mutants of interferon (IFN). Our model quantitatively reproduces all the experimental results, illustrating how chimeras using mutants of IFN with reduced affinity exhibit enhanced selectivity against cell overexpressing EGF receptor. We also investigate how chimeric selectivity can be improved based on the balance between affinity rates, receptor abundance, activity of ligand subunits, and linker length between subunits. The simplicity and generality of the model facilitate a straightforward application to other chimeric constructs, providing a quantitative systematic design and optimization of these selective drugs against certain cell-based diseases, such as Alzheimer's and cancer.

CD30 Expression in Diffuse Large B-Cell Lymphoma and Its Relation to Important Clinical and Biological Disease Features

AbstractAbstract 1592 Background:CD30 is a well-known diagnostic marker in both anaplastic large cell lymphoma (ALCL) and classical Hodgkin's lymphoma (CHL). Recently the chimeric drug brentuximab vedotin that combines an anti-CD30 monoclonal antibody with the anti-tubulin agent monomethyl auristatin E demonstrated activity in patients with relapsed ALCL and CHL. Previous observational studies have suggested that CD30 may be expressed in 10 to 20% of DLBCLs. It is possible that CD30+ DLBCLs may show different biologic behavior and be amenable to anti-CD30 therapy. The aim of this study was to determine the prevalence of CD30 expression in DLBCL by immunohistochemistry and explore possible relationships with important clinical and biologic variables of DLBCL. Methods:We retrospectively identified cases of DLBCL diagnosed between July 2003 and July 2012 at our institution. Eligible cases included patients with diagnosis of DLBCL irrespective of anatomic site or tumor stage. The diagnosis of DLBCL was based on the current WHO 2008 criteria. The following large B cell lymphoma subtypes were excluded from this analysis: post-transplant lymphoproliferative disorders with DLBCL morphology, Primary Mediastinal large cell lymphoma and the unclassifiable lymphomas with features intermediate between either DLBCL and Burkitt’s lymphoma or between DLBCL and Hodgkin’s lymphoma. Immunohistochemistry was performed as part of the routine workup of the cases (Monoclonal Mouse Anti-Human CD30, Dako) and CD30 was considered positive when ≥30% of neoplastic cells stained positive. DLBCLs were classified into germinal center (GC) or non-GC subtypes applying the Hans algorithm. Logistic regression analysis was performed to assess association between selected variables and CD30 expression. Results:A total of 333 cases of DLBCL were eligible for this study and of these 148 cases (44.4%) had CD30 results available. Selected demographic, clinical and histological characteristics were similar between cases on which CD30 IHC was performed compared to those in which CD30 IHC was not performed (data not shown), arguing against a selection bias in the performance of CD30 immunohistochemistry in these cases. Twenty-three percent (95% CI: 16.2% – 29.8%) of DLBCL tumors expressed CD30. CD30 expression was not significantly different between females and males (27.6% and 20.0% respectively, p = 0.28). The patients with CD30+ DLBCLs were 11.6 years younger than those with CD30- DLBCLs (95% CI: 5.3 – 17.9 years). The optimal cutoff age for CD30 expression was 47 years (ROC area under the curve: 0.70, p < 0.001). CD30 expression was more frequent in nodal and BCL2+ DLBCLs (Table 1). There was a non-significant difference between the expression of CD30 in non-GC type compared to GC type DLBCL with a pronounced trend for higher proportion of CD30 positivity in non-GC DLBCL (Table 1). CD30 expression was not significantly different in Epstein-Barr virus positive (EBV) compared to EBV negative DLBCLs (Table 1). Conclusions:CD30 is expressed in approximately 20% of all DLBCL and is more frequently expressed in younger patients and in BCL2+ DLBCLs. Although statistical significance was not reached, a trend towards more frequent CD30 expression in non-GC DLBCLs was observed. The increased expression of CD30 in the younger age group is intriguing, as other CD30+ neoplasms (CD30+ ALCL, CHL, and embryonal carcinoma) are also commonly observed in younger patients. The development of brentuximab vedotin and its well established effectiveness in other types of relapsed lymphomas opens the possibility of its applicability in CD30+ DLBCLs.Table 1CD30 expression by age, site, BCL2 expression, subtype of DLBCL and EBV status.Variable**nCD30+ n (%)OR (95% CI)Age4.4 (1.9–10.2)≤47 years6424 (37.5)>47 years8410 (10.3)Site3.0 (1.3–7.0)Nodal5217 (32.7)Extra nodal9617 (17.7)BCL25.2 (1.4–19.0)Positive6419 (29.7)Negative403 (7.5)Type2.5 (0.9–6.8)Non-GC5515 (28.8)GC507 (14.0)EBV1.7 (0.3–9.3)Negative446 (18)Positive182 (11)The second category listed is the reference category.Table 2Multivariate analysis of association of CD30 expression with age, site, BCL2 expression, and subtype of DLBCL.Independent variablesOR (95% CI)Age ≤47 years10.0 (2.5–40.1)Nodal DLBCL1.1 (0.3–4.0)BCL2 positive7.7 ( 1.4–43.9)Non-GC2.1 (0.6–7.9)N = 78. Dependent variable: CD30 expression. R2 = 0.35, Hosmer-Lemeshow goodness of fit p-value = 0.54. Disclosures:No relevant conflicts of interest to declare.

Rituximab in Membranous Nephropathy

Rituximab, a B cell–depleting anti-CD20 chimeric monoclonal antibody, is Food and Drug Administration approved in the United States for the treatment of certain lymphomas, rheumatoid arthritis, and granulomatous and microscopic polyangiitis. It has been used additionally in a wide variety of

A New Chimeric Drug Delivery Nano System (chi-aDDnS) Composed of PAMAM G 3.5 Dendrimer and Liposomes as Doxorubicin's Carrier. &lt;I&gt;In Vitro&lt;/I&gt; Pharmacological Studies

Chimeric advanced Drug Delivery nano Systems (chi-aDDnSs) could be defined as mixed nanosystems due to the combination process of nanobiomaterials and can offer advantages as drug carriers. The role of the release modulator from the liposomal system is undertaken by the dendrimer molecules leading to new pharmacokinetic and, probably, pharmacological properties of the chimeric system. In this work, a conventional DOPC/DPPG liposomal system and a new chi-aDDnS composed of liposomes (DOPC/DPPG) incorporating PAMAM G3,5 has been developed, Doxorubicin (Dox) was loaded in the systems and the final formulations were lyophilized. The physicochemical (spectroscopic and calorimetric) investigation concerning the chi-aDDnS, revealed a strong interaction between both lipophilic and hydrophilic parts of the liposomal membrane and the dendrimer, with the induction of multiple energetic states. These states are probably the basis of higher Dox encapsulation and slower release rate compared to the respective conventional liposome. These results, in conjunction with the increase in TI observed in two investigated cancer cell lines (i.e., MB231 and MCF7), compared to the respective conventional liposomal system and to the free Dox, make this new chi-aDDnS the basic candidate for further in vivo investigations.

Modulating cGMP in heart failure by novel natriuretic peptides

An emerging concept in cardiorenal therapeutics is the design and synthesis of chimeric drugs that are single-chemical entities that combine structural and biological components of different molecules resulting in novel agents possessing highly desirable properties. Such a strategy optimizes favorable actions of a least two different molecules and often reduces unwanted adverse effects. We recently reported the design, synthesis and biological actions of a novel chimeric natriuretic peptide (NP) fusing the 22-amino acid (AA) sequence of mature C-type natriuretic peptide (CNP), a member of the NP family that is highly conserved among species, with the 15-AA C-terminus of Dendroaspis natriuretic peptide (DNP) that was isolated from the venom of the eastern green mamba snake (Dendroaspis angusticeps). The rationale of the design of this novel chimeric NP was based upon our knowledge that CNP, principally an endothelial cell derived peptide, has favorable venorelaxing properties that would unload the heart in states of volume overload but when compared to atrial NP (ANP), B-type NP (BNP) or urodilatin (URO), which are marked arterial vasodilators, would be less hypotensive thus better preserving renal perfusion pressure. Such hemodynamic properties are a consequence of CNP activation of the NP receptor-B (NPR-B) that is highly expressed in veins as compared to arteries. In contrast, ANP and BNP which function via the NP receptor-A (NPR-A) principally vasorelax arteries where NPR-A is highly expressed. A therapeutic limitation of the use of CNP in volume overload states is that in contrast to ANP and BNP, CNP lacks renal actions limiting its utility in states of sodium and water retention or altered glomerular function. The second principle in the design of CD-NP was based upon our understanding of DNP. Indeed, previous studies from our laboratory have demonstrated that DNP is potently natriuretic and diuretic but also markedly hypotensive. More recently, studies have established that DNP like ANP and BNP is a ligand for NPR-A. Further, Lisy et al have reported that the 15-AA C-terminus of DNP possessed mild natriuretic and diuretic actions, which provided the rationale for the hypothesis that the C-terminus of DNP in a chimeric design would provide CNP with the ability to activate NPR-A and transform CNP into a natriuretic and diuretic peptide lacking significant hypotensive actions. Indeed, in recent studies in cells overexpressing either NPR-A or NPR-B, CD-NP activated both NPR-B and NPR-A with predominate stimulation being NPR-B. Specifically, CD-NP was able to activate in cells expressing either NPR-A or NPR-B the generation of cyclic guanosine monophosphate (cGMP) that is the second messenger for both NP receptors. Here we will review both preclinical development and the first clinical studies including first in humans and studies in human heart failure.

Design and Applications of Bifunctional Small Molecules: Why Two Heads Are Better Than One

Induction of protein--protein interactions is a daunting challenge, but recent studies show promise for small molecules that specifically bring two or more protein molecules together for enhanced or novel biological effect. The first such bifunctional molecules were the rapamycin- and FK506-based "chemical inducers of dimerization", but the field has since expanded with new molecules and new applications in chemical genetics and cell biology. Examples include coumermycin-mediated gyrase B dimerization, proteolysis targeting chimeric molecules (PROTACs), drug hybrids, and strategies for exploiting multivalency in toxin binding and antibody recruitment. This Review discusses these and other advances in the design and use of bifunctional small molecules and potential strategies for future systems.

Patenting antibodies

Antibody technology has advanced a long way since the early days of Kohler and Milstein's antibody-secreting murine hybridomas1; and although Kohler and Milstein's invention was not patented, patent protection for the new generation of murine, chimeric, humanized and human antibody-based drugs is essential to safeguard their future development.

New vector innovation for drug delivery: development of fusigenic non-viral particles.

Efficient and minimally invasive drug delivery systems have been developed to treat intractable human diseases. One approach has been the development of chimeric vector systems combining at least two different vector systems. Based on this concept, chimeric drug delivery systems that combine viral and non-viral features have been developed. Fusigenic non-viral particles have been constructed by conferring viral fusion proteins onto non-viral vectors. HVJ (hemagglutinating virus of Japan; Sendai virus)-liposomes were constructed by the combination of DNA-loaded liposomes with a fusigenic envelope derived from HVJ (hemagglutinating virus of Japan, Sendai virus). Reconstituted HVJ-liposomes were also developed by the insertion of isolated fusion proteins of HVJ into DNA-loaded liposomes. Recently, the technology has been developed to incorporate macromolecules directly into inactivated HVJ particles without liposomes. The resulting HVJ envelope vector introduced plasmid DNA, efficiently and rapidly into both cultured cells in vitro and organs in vivo. Furthermore, proteins, synthetic oligonucleotides and drugs have also been effectively introduced into cells using the HVJ envelope vector. The HVJ envelope vector will be a promising tool for both ex vivo and in vivo gene therapy experiments.

Imaging gene expression in the brain with peptide nucleic acid (PNA) antisense radiopharmaceuticals and drug targeting technology

Antisense oligomers are potential pharmaceutical and radiopharmaceutical agents that can be used to modulate and image gene expression. Progress with in vivogene targeting using antisense-based therapeutics has been slower than expected during the last decade, owing to poor trans-cellular delivery of antisense agents. This chapter suggests that if antisense pharmacology is merged with drug targeting technology, then membrane barriers can be circumvented and antisense agents can be delivered to tissues in vivo. Without the application of drug targeting, the likelihood of success for an antisense drug development program is low, particularly for the brain which is protected by the blood-brain barrier (BBB). Among the different classes of antisense agents, peptide nucleic acids (PNA) present advantages for in vivoapplications over conventional and modified oligodeoxynucleotides (ODN), including phosphorothioates (PS)-ODN. Some advantages of PNAs include their electrically neutral backbone, low toxicity to neural cells, resistance to nucleases and peptidases, and lack of binding to plasma proteins. PNAs are poorly transported through cellular membranes, however, including the BBB and the brain cell membrane (BCM). Because the mRNA target for the antisense agent lies within the cytosol of the target cell, the BBB and the BCM must be circumvented in vivo, which ispossible with the use of chimeric peptide drug targeting technology. Chimeric peptides are formed by conjugation of a non-transportable drug, such as a PNA, to a drug delivery vector. The vector undergoes receptor-mediated transcytosis (RMT) through the BBB and receptor-mediated endocytosis through the BCM in vivo. When labeled with a radioisotope (e.g., 125I or 111In), the antisense chimeric peptide provides imaging of gene expressionin the brain in vivoin a sequence-specific manner. Further development of antisense radiopharmaceutical agents may allow for in vivoimaging of genes in pathological states, and may provide tools for the analysis of novel genes with functional genomics.

Synthesis and pharmacological properties of 2-[S-acetylthiorphan]-1,3- diacylaminopropan-2-ol derivatives as chimeric lipid drug carriers containing an enkephalinase inhibitor.

The design of 1,3-dacylaminopropan-2-ols as CNS-directed carrier groups is based on their resemblance to endogenous lipids and the properties of pseudotriglyceride esters to facilitate the brain penetration of therapeutic agents. 2-[S-acetylthiorphan]-1,3-diacylaminopropan-2-ols, differing from the nature of 1,3-acyl chains, were synthesized and evaluated in vivo using the hot-plate jump test. The compounds exhibited naloxone reversible analgesic properties. The effects were superior to those of parent compounds thiorphan and S-acetylthiorphan. The palmitoyl derivative showed also activity at 0.8 mmol/kg after oral administration. Like acetorphan, a thiorphan prodrug, these compounds were poor substrates for brain enkephalinase, suggesting the release of the pharmacological active inhibitor at the site of action in the brain.

Targeting Drugs and Toxins to the Brain: Magic Bullets

This chapter highlights the relevant findings in toxin and cancer research and introduces the magic bullets as antineoplastic drugs. A magic bullet is a bifunctional substance that is directed with high specificity to diseased cells and possesses a medication to overcome disease. The toxin molecule displays two of the cardinal features of a magic bullet. It has a binding domain that positions the molecule on target tissue, and it has an intracellularly acting domain that alters tissue function. In these respects, a molecule can serve as a model. All of the magic bullets that are described use an antibody as a tissue-targeting domain, if these agents employ an antibody at all. The magic bullets use an antibody as a tissue-targeting domain, if the agents employ an antibody at all and considering that, there is an alternate way to envision chimeras, and the products might prove to be a new class of drugs with broad therapeutic utility. Chimeric drugs are designed to attack neuroblastomas and pheochromocytomas. The limitations do not appear to be in the drugs, but rather in the ability of neuroscientists to adopt a new technology and exploit it fully. For most of the potent protein toxins, conventional antibody therapy is of no practical value when vulnerable cells in the patient have internalized the poison.