Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery

Cryptophycins are potent tubulin polymerization inhibitors with picomolar antiproliferative potency in vitro and activity against multidrug-resistant (MDR) cancer cells. Because of neurotoxic side effects and limited efficacy in vivo, cryptophycin-52 failed as a clinical candidate in cancer treatment. However, this class of compounds has emerged as attractive payloads for tumor-targeting applications. In this study, cryptophycin was conjugated to the cyclopeptide c(RGDfK), targeting integrin αvβ3, across the protease-cleavable Val-Cit linker and two different self-immolative spacers. Plasma metabolic stability studies in vitro showed that our selected payload displays an improved stability compared to the parent compound, while the stability of the conjugates is strongly influenced by the self-immolative moiety. Cathepsin B cleavage assays revealed that modifications in the linker lead to different drug release profiles. Antiproliferative effects of Arg-Gly-Asp (RGD)–cryptophycin conjugates were evaluated on M21 and M21-L human melanoma cell lines. The low nanomolar in vitro activity of the novel conjugates was associated with inferior selectivity for cell lines with different integrin αvβ3 expression levels. To elucidate the drug delivery process, cryptophycin was replaced by an infrared dye and the obtained conjugates were studied by confocal microscopy.

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In Vitro and In Vivo Characterization of Tebipenem, an Oral Carbapenem

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02240-19 ◽

2020 ◽

Vol 64 (8) ◽

Author(s):

Nicole Cotroneo ◽

Aileen Rubio ◽

Ian A. Critchley ◽

Chris Pillar ◽

Michael J. Pucci

Keyword(s):

Bacterial Resistance ◽

Unmet Need ◽

Multidrug Resistant ◽

Oral Agent ◽

Gram Negative ◽

Improved Stability ◽

Tebipenem Pivoxil ◽

Tract Infections

ABSTRACT The continued evolution of bacterial resistance to the β-lactam class of antibiotics has necessitated countermeasures to ensure continued effectiveness in the treatment of infections caused by bacterial pathogens. One relatively successful approach has been the development of new β-lactam analogs with advantages over prior compounds in this class. The carbapenems are an example of such β-lactam analogs possessing improved stability against β-lactamase enzymes and, therefore, a wider spectrum of activity. However, all carbapenems currently marketed for adult patients are intravenous agents, and there is an unmet need for an oral agent to treat patients that otherwise do not require hospitalization. Tebipenem pivoxil hydrobromide (tebipenem-PI-HBr or SPR994) is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) Gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacterales. Tebipenem-PI-HBr is currently in development for the treatment of complicated urinary tract infections (cUTI). Microbiological data are presented here that demonstrate equivalency of tebipenem with intravenous carbapenems such as meropenem and support its use in infections in which the potency and spectrum of a carbapenem are desired. The results from standard in vitro microbiology assays as well as efficacy in several in vivo mouse infection models suggest that tebipenem-PI-HBr could be a valuable oral agent available to physicians for the treatment of infections, particularly those caused by antibiotic-resistant Gram-negative pathogens.

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Soft Cationic Nanoparticles for Drug Delivery: Production and Cytotoxicity of Solid Lipid Nanoparticles (SLNs)

Applied Sciences ◽

10.3390/app9204438 ◽

2019 ◽

Vol 9 (20) ◽

pp. 4438 ◽

Cited By ~ 14

Author(s):

Amélia Silva ◽

Carlos Martins-Gomes ◽

Tiago Coutinho ◽

Joana Fangueiro ◽

Elena Sanchez-Lopez ◽

...

Keyword(s):

Drug Delivery ◽

Surface Properties ◽

Cell Lines ◽

Solid Lipid Nanoparticles ◽

Lipid Nanoparticles ◽

Cationic Lipids ◽

Solid Lipid ◽

Mcf 7

The surface properties of nanoparticles have decisive influence on their interaction with biological barriers (i.e., living cells), being the concentration and type of surfactant factors to have into account. As a result of different molecular structure, charge, and degree of lipophilicity, different surfactants may interact differently with the cell membrane exhibiting different degrees of cytotoxicity. In this work, the cytotoxicity of two cationic solid lipid nanoparticles (SLNs), differing in the cationic lipids used as surfactants CTAB (cetyltrimethylammonium bromide) or DDAB (dimethyldioctadecylammonium bromide), referred as CTAB-SLNs and DDAB-SLNs, respectively, was assessed against five different human cell lines (Caco-2, HepG2, MCF-7, SV-80, and Y-79). Results showed that the cationic lipids used in SLN production highly influenced the cytotoxic profile of the particles, with CTAB-SLNs being highly cytotoxic even at low concentrations (IC50 < 10 µg/mL, expressed as CTAB amount). DDAB-SLNs produced much lower cytotoxicity, even at longer exposure time (IC50 from 284.06 ± 17.01 µg/mL (SV-80) to 869.88 ± 62.45 µg/mL (MCF-7), at 48 h). To the best of our knowledge, this is the first report that compares the cytotoxic profile of CTAB-SLNs and DDAB-SLNs based on the concentration and time of exposure, using different cell lines. In conclusion, the choice of the right surfactant for biological applications influences the biocompatibility of the nanoparticles. Regardless the type of drug delivery system, not only the cytotoxicity of the drug-loaded nanoparticles should be assessed, but also the blank (non-loaded) nanoparticles as their surface properties play a decisive role both in vitro and in vivo.

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Synthesis and biological evaluation of carbon-substituted C-4 derivatives of podophyllotoxin

Canadian Journal of Chemistry ◽

10.1139/v96-187 ◽

1996 ◽

Vol 74 (9) ◽

pp. 1704-1708 ◽

Cited By ~ 7

Author(s):

Yvonne Lear ◽

Tony Durst

Keyword(s):

Antitumour Activity ◽

Human Colon ◽

Boron Trifluoride Etherate ◽

Multidrug Resistant ◽

Resistant Cell ◽

Biological Evaluation ◽

Colon Cell ◽

Colon Cell Line

Several C-4 carbon-substituted analogues of podophyllotoxin, 1, were prepared by treatment of 1 with allyltrimethylsilane or trimethylsilylcyanide in the presence of boron trifluoride etherate. Alternatively, carbon substituents were introduced via additions to the carbobenzyloxy-protected C-4′-dimethylated podophyllotoxone. These 4′-dimethylated derivatives showed promising in vitro antitumour activity and were equally active against human colon cell line HT116 and two multidrug resistant cell lines. The alcohol 6 was evaluated in vivo but was found to be inactive. Key words: podophyllotoxin analogues, podophyllotox-4-one, C4 carbon substituted podophyllotoxins.

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Doxorubicin/Nucleophosmin Binding Protein-Conjugated Nanoparticle Enhances Anti-leukemia Activity in Acute Lymphoblastic Leukemia Cells in vitro and in vivo

Frontiers in Pharmacology ◽

10.3389/fphar.2021.607755 ◽

2021 ◽

Vol 12 ◽

Author(s):

Donghui Gan ◽

Yuwen Chen ◽

Zhengjun Wu ◽

Liping Luo ◽

Shimuye Kalayu Yirga ◽

...

Keyword(s):

Drug Delivery ◽

Acute Lymphoblastic Leukemia ◽

Drug Delivery System ◽

Delivery System ◽

Binding Protein ◽

Lymphoblastic Leukemia ◽

Multidrug Resistant ◽

Apoptosis Induction

Acute lymphoblastic leukemia (ALL) is an aggressive malignancy. Adults with ALL have more than 50% relapse rates. We have previously validated that overexpression of nucleophosmin (NPM) is involved in the multidrug resistance (MDR) development during ALL; and a synthetically engineered recombinant NPM binding protein (NPMBP) has been developed in our group; NPMBP and doxorubicin (DOX) can be conjugated in a nanoparticle-based drug delivery system named DOX-PMs-NPMBP to counteract MDR during ALL. Here, we evaluated the antileukemia potential of DOX-PMs-NPMBP in resistant ALL cells. This study demonstrates that DOX-PMs-NPMBP significantly enhances chemosensitivity to DOX in ALL cells. Despite at variable concentrations, both resistant and primary ALL cells from relapsed patients were sensitive to DOX-PMs-NPMBP. In detail, the half maximal inhibitory concentration (IC50) values of DOX-PMs-NPMBP were between 1.6- and 7.0-fold lower than those of DOX in cell lines and primary ALL cells, respectively; and apoptotic cells ratio was over 2-fold higher in DOX-PMs-NPMBP than DOX. Mechanistically, p53-driven apoptosis induction and cell cycle arrest played essential role in DOX-PMs-NPMBP-induced anti-leukemia effects. Moreover, DOX-PMs-NPMBP significantly inhibited tumor growth and prolonged mouse survival of ALL xenograft models; and no systemic toxicity occurrence was observed after treatment during follow-up. In conclusion, these data indicate that DOX-PMs-NPMBP may significantly exert growth inhibition and apoptosis induction, and markedly improve DOX antileukemia activity in resistant ALL cells. This novel drug delivery system may be valuable to develop as a new therapeutic strategy against multidrug resistant ALL.

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Octreotide-conjugated silver nanoparticles for active targeting of somatostatin receptors and their application in a nebulized rat model

Nanotechnology Reviews ◽

10.1515/ntrev-2022-0021 ◽

2021 ◽

Vol 11 (1) ◽

pp. 266-283

Author(s):

Ahmed A. H. Abdellatif ◽

Riaz A. Khan ◽

Ahmad H. Alhowail ◽

Abdulmajeed Alqasoumi ◽

Sultan M. Sajid ◽

...

Keyword(s):

Drug Delivery ◽

Silver Nanoparticles ◽

Cell Lines ◽

Somatostatin Receptors ◽

Somatostatin Analogs ◽

Drug Uptake ◽

Emission Spectrometry ◽

Dependent Manner

Abstract Drug uptake and distribution through cell–receptor interactions are of prime interest in reducing the adverse effects and increasing the therapeutic effectiveness of delivered formulations. This study aimed to formulate silver nanoparticles (AgNPs) conjugated to somatostatin analogs for specific delivery through somatostatin receptors (SSTRs) expressed on cells and by nebulizing the prepared AgNPs formulations into lung cells for in vivo application. AgNPs were prepared using the citrate reduction method, yielding AgNPs–CTT, which was further chemically conjugated to octreotide (OCT) to form AgNPs–OCT through an amide linkage. The AgNPs–OCT formulation was coated using alginate to yield a carrier, AgNPs–OCT–Alg, feasible for drug delivery through nebulization. AgNPs were uniform in size with an acceptable range of zeta potential. Furthermore, the concentrations of AgNP formulations were found safe for the model cell lines used, and cell proliferation was significantly reduced in a dose-dependent manner (p < 0.05). In the healthy lung tissues, AgNPs–OCT–Alg accumulated at a concentration of 0.416 ± 5.7 mg/kgtissue, as determined via inductively coupled plasma optical emission spectrometry. This study established the accumulation of AgNPs, specifically the AgNPs–OCT–Alg, in lung tissues, and substantiated the active, specific, and selective targeting of SSTRs at pulmonary sites. The anticancer efficacy of the formulations was in vitro tested and confirmed in the MCF-7 cell lines. Owing to the delivery suitability and cytotoxic effects of the AgNPs–OCT–Alg formulation, it is a potential drug delivery formulation for lung cancer therapy in the future.

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A Corollary of Nanoporous Carrier Drug Delivery System: An Updated Perspective

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2020.13.5.1 ◽

2020 ◽

Vol 13 (5) ◽

pp. 5047-5061

Author(s):

Om M Bagade ◽

Shashikant N Dhole ◽

Praveen D Chaudhar

Keyword(s):

Drug Delivery ◽

Drug Delivery System ◽

Delivery System ◽

Skin Irritation ◽

Extended Period ◽

Spherical Particles ◽

In Vivo Evaluation ◽

Improved Stability

Nanosponges have come into sight as one of the most promising fields of science because of their perceived applications in controlled drug delivery. It has been increasingly investigated to achieve targeted and sustained release of drugs. Nanosponges are one of the novel drug delivery system, which is gaining popularity now days because of their perceived application in controlled and site-specific drug delivery. The fundamental appeal of the nanosponge technology arises from the difficulty experienced with conventional formulations in releasing active ingredients over an extended period of time, unpleasant odor, greasiness and skin irritation. They are tiny sponge-like spherical particles with a large porous surface and are believed to contribute towards reduced side effects, improved stability, increased elegance and enhanced formulation flexibility. The present investigation in the appraisal describes nanosponge technology embracing its method of preparation, characterization, in-vitro and in-vivo evaluation methods along with recent research and future potential.

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Synthesis and Biological Evaluation (in Vitro and in Vivo) of Cyclic Arginine–Glycine–Aspartate (RGD) Peptidomimetic–Paclitaxel Conjugates Targeting Integrin αVβ3

Journal of Medicinal Chemistry ◽

10.1021/jm301058f ◽

2012 ◽

Vol 55 (23) ◽

pp. 10460-10474 ◽

Cited By ~ 54

Author(s):

Raffaele Colombo ◽

Michele Mingozzi ◽

Laura Belvisi ◽

Daniela Arosio ◽

Umberto Piarulli ◽

...

Keyword(s):

Integrin Αvβ3 ◽

Biological Evaluation ◽

Synthesis And Biological Evaluation

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Design, Synthesis and In-Vitro Biological Evaluation of Antofine and Tylophorine Prodrugs as Hypoxia-Targeted Anticancer Agents

Molecules ◽

10.3390/molecules26113327 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3327

Author(s):

Ziad Omran ◽

Chris P. Guise ◽

Linwei Chen ◽

Cyril Rauch ◽

Ashraf N. Abdalla ◽

...

Keyword(s):

Anticancer Agents ◽

Biological Activities ◽

Multidrug Resistant ◽

Biological Evaluation ◽

High Chemical ◽

Design Synthesis ◽

Hypoxic Conditions ◽

Cancerous Cell

Phenanthroindolizidines, such as antofine and tylophorine, are a family of natural alkaloids isolated from different species of Asclepiadaceas. They are characterized by interesting biological activities, such as pronounced cytotoxicity against different human cancerous cell lines, including multidrug-resistant examples. Nonetheless, these derivatives are associated with severe neurotoxicity and loss of in vivo activity due to the highly lipophilic nature of the alkaloids. Here, we describe the development of highly polar prodrugs of antofine and tylophorine as hypoxia-targeted prodrugs. The developed quaternary ammonium salts of phenanthroindolizidines showed high chemical and metabolic stability and are predicted to have no penetration through the blood–brain barrier. The designed prodrugs displayed decreased cytotoxicity when tested under normoxic conditions. However, their cytotoxic activity considerably increased when tested under hypoxic conditions.

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Design, Synthesis, and Biological Evaluation of Novel N-Acylhydrazone Bond Linked Heterobivalent β-Carbolines as Potential Anticancer Agents

Molecules ◽

10.3390/molecules24162950 ◽

2019 ◽

Vol 24 (16) ◽

pp. 2950 ◽

Cited By ~ 3

Author(s):

Chen ◽

Guo ◽

Ma ◽

Chen ◽

Fan ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Anticancer Agents ◽

Chorioallantoic Membrane ◽

Cancer Cell Lines ◽

Biological Evaluation ◽

In Vivo Model ◽

Ic50 Values

Utilizing a pharmacophore hybridization approach, we have designed and synthesized a novel series of 28 new heterobivalent β-carbolines. The in vitro cytotoxic potential of each compound was evaluated against the five cancer cell lines (LLC, BGC-823, CT-26, Bel-7402, and MCF-7) of different origin—murine and human, with the aim of determining the potency and selectivity of the compounds. Compound 8z showed antitumor activities with half-maximal inhibitory concentration (IC50) values of 9.9 ± 0.9, 8.6 ± 1.4, 6.2 ± 2.5, 9.9 ± 0.5, and 5.7 ± 1.2 µM against the tested five cancer cell lines. Moreover, the effect of compound 8z on the angiogenesis process was investigated using a chicken chorioallantoic membrane (CAM) in vivo model. At a concentration of 5 μM, compound 8z showed a positive effect on angiogenesis. The results of this study contribute to the further elucidation of the biological regulatory role of heterobivalent β-carbolines and provide helpful information on the development of vascular targeting antitumor drugs.

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Infection Responsive Smart Delivery of Antibiotics Using Recombinant Spider Silk Nanospheres

Pharmaceutics ◽

10.3390/pharmaceutics13091358 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1358

Author(s):

Pranothi Mulinti ◽

Jacob Shreffler ◽

Raquib Hasan ◽

Michael Dea ◽

Amanda E. Brooks

Keyword(s):

Drug Delivery ◽

Drug Release ◽

Spider Silk ◽

Popular Science ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Bacterial Strains ◽

Antibiotic Drug

Frequent and inappropriate usage of antibiotics has changed the natural evolution of bacteria by reducing susceptibility and increasing resistance towards antibacterial agents. New resistance mechanisms evolved in the response to host defenses and pharmaceutical interventions are threatening our ability to treat common infections, resulting in increased mortality. In the face of this rising epidemic, antibiotic drug discovery, which has long been overlooked by big pharma, is reaching a critical low. Thus, the development of an infection-responsive drug delivery system, which may mitigate multidrug resistance and preserve the lifetime of our current antibiotic arsenal, has garnered the attention of both popular science and funding agencies. The present work describes the development of a thrombin-sensitive linker embedded into a recombinant spider silk copolymer to create a nanosphere drug delivery vehicle. Recent studies have suggested that there is an increase in thrombin-like activity during Staphylococcus aureus infection; thus, drug release from this new “smart” nanosphere can be triggered in the presence of infection. A thrombin sensitive peptide (TSP) was synthesized, and the thrombin cleavage sensitivity was determined by HPLC. The results showed no cleavage of the peptide when exposed to human serum whereas the peptide was cleaved when incubated with S. aureus exudate. Subsequently, the peptide was coupled with a silk copolymer via EDC-NHS chemistry and formulated into nanospheres encapsulating antibiotic vancomycin. These nanospheres were evaluated for in vitro infection-responsive drug release and antimicrobial activity. Finally, the drug responsive nanospheres were assessed for efficacy in an in vivo septic arthritis model. Our study provides evidence that the protein conjugate was enzyme responsive and can be used to formulate targeted drug release to combat infections against multidrug-resistant bacterial strains.

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