Combinatorial Screening for Specific Drug Solubilizers with Switchable Release Profiles (original) (raw)
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The design and synthesis of a photo-controlled, peptide-based potential drug carrier
TURKISH JOURNAL OF CHEMISTRY
Our focus in this study is on the design and synthesis of a light-responsive peptide-based nanocarrier in order to develop effective and biocompatible drug delivery systems. The synthesized nanocarrier is basically composed of peptide amphiphiles comprising a micelle forming a Pro-Pro-Pro-Lys-Lys-Lys peptide sequence with an attached anthracene fluorophore. Anthracene containing an inner core of the micelle can serve as a storage site for poorly watersoluble drugs. Moreover, anthracenes that come in close proximity with the formation of micellar structures can undergo photodimerization upon irradiation at 365 nm, which disrupts the micelle structures formed by the self-assembly of the peptide amphiphiles. Therefore, if a drug is encapsulated within the hydrophobic core of this peptidic carrier system, its release can be induced by the controlled exposure of the anthracene moiety to UV light.
Proceedings of the National Academy of Sciences
Supramolecular self-assemblies of hydrophilic macromolecules functionalized with hydrophobic, structure-directing components have long been used for drug delivery. In these systems, loading of poorly soluble compounds is typically achieved through physical encapsulation during or after formation of the supramolecular assembly, resulting in low encapsulation efficiencies and limited control over release kinetics, which are predominately governed by diffusion and carrier degradation. To overcome these limitations, amphiphilic prodrugs that leverage a hydrophobic drug as both the therapeutic and structure-directing component can be used to create supramolecular materials with higher loading and controlled-release kinetics using biodegradable or enzymatically cleavable linkers. Here, we report the design, synthesis, and characterization of a library of supramolecular polymer prodrugs based on poly(ethylene glycol) (PEG) and the proregenerative drug 1,4-dihydrophenonthrolin-4-one-3-carbo...
Novel cleavable cell-penetrating peptide-drug conjugates: synthesis and characterization
Journal of Peptide Science, 2014
We report the first drug conjugate with a negatively charged amphipathic cell-penetrating peptide. Furthermore, we compare two different doxorubicin cell-penetrating peptide conjugates, which are both unique in their properties, due to their net charge at physiological pH, namely the positively charged octaarginine and the negatively charged proline-rich amphipathic peptide. These conjugates were prepared exploiting a novel heterobifunctional crosslinker to join the N-terminal cysteine residue of the peptides with the aliphatic ketone of doxorubicin. This small linker contains an activated thiol as well as aminooxy functionality, capable of generating a stable oxime bond with the C-13 carbonyl group of doxorubicin. The disulfide bond formed between the peptide and doxorubicin enables the release of the drug in the cytosol, as confirmed by drug-release studies performed in the presence of glutathione. Additionally, the cytotoxicity as well as the cellular uptake and distribution of this tripartite drug delivery system was investigated in MCF-7 and HT-29 cell lines.
pH-Sensitive Drug-Conjugates on Water-Soluble Polymer Frameworks
Macromolecular Chemistry and Physics, 2014
A potent synthetic methodology is introduced to generate a useful intermediate for the preparation of 'smart' polymeric pro-drugs. Herein, living anionic block polymerization of ethylene oxide (EO) and N-phenylmaleimide (N-PMI), as well as the Gabriel process, are introduced. Hydrazinolysis of the resulting poly(ethylene oxide)-block-poly(N-PMI) (PEO-b-P N-PMI) using hydrazine under acidic conditions leads to the production of PEO-based frameworks with hydrazide (HZ) groups. The HZ groups are found to effect the formation of an acidsensitive bond in reactions with medicines or drugs under neutral conditions (pH 7.2). The PEO-HZ intermediate, which shows a strong triplet splitting patterned chemical shift in the range δ = 6.5-8.5 ppm, represents the most powerful material employed for mass production of smart polymeric pro-drugs while controlling the drug-loading yield. Watersoluble "smart" polymeric pro-drugs, such as poly(ethylene oxide)-doxorubicin (PEO-HZ-Dox), poly(ethylene oxide)methotrexate (PEO-HZ-MTX), and poly(ethylene oxide)-folate (PEO-HZ-FA) conjugates, show excellent acid-sensitive release profi les in water or alcohol at pH 4.5.
Polymer–drug conjugates for novel molecular targets
Nanomedicine, 2010
Polymer therapeutics can be already considered as a promising field in the human healthcare context. The discovery of the enhanced permeability and retention effect by Maeda, together with the modular model for the polymer–drug conjugate proposed by Ringsdorf, directed the early steps of polymer therapeutics towards cancer therapy. Orthodox anticancer drugs were preferentially chosen in the development of the first conjugates. The fast evolution of polymer chemistry and bioconjugation techniques, and a deeper understanding of cell biology has opened up exciting new challenges and opportunities. Four main directions have to be considered to develop this ‘platform technology’ further: the control of the synthetic process, the exhaustive characterization of the conjugate architectures, the conquest of combination therapy and the disclosure of new therapeutic targets. We illustrate in this article the exciting approaches offered by polymer–drug conjugates beyond classical cancer therapy...
PEG-polypeptide Block Copolymers as pH-responsive Endosome-Solubilizing Drug Nanocarriers
Molecular Pharmaceutics, 2014
Herein we report the potential of click chemistry-modified polypeptide-based block copolymers for the facile fabrication of pH-sensitive nanoscale drug delivery systems. PEG−polypeptide copolymers with pendant amine chains were synthesized by combining N-carboxyanhydridebased ring-opening polymerization with post-functionalization using azide−alkyne cycloaddition. The synthesized block copolymers contain a polypeptide block with amine-functional side groups and were found to self-assemble into stable polymersomes and disassemble in a pH-responsive manner under a range of biologically relevant conditions. The selfassembly of these block copolymers yields nanometer-scale vesicular structures that are able to encapsulate hydrophilic cytotoxic agents like doxorubicin at physiological pH but that fall apart spontaneously at endosomal pH levels after cellular uptake. When drug-encapsulated copolymer assemblies were delivered systemically, significant levels of tumor accumulation were achieved, with efficacy against the triple-negative breast cancer cell line, MDA-MB-468, and suppression of tumor growth in an in vivo mouse model.
ACS Omega
In recent decades, drug delivery systems (DDSs) based on polymer nanoparticles have been explored due to their potential to deliver drugs with poor water solubility. Some of the limitations of nanoparticle-based DDSs can be overcome by developing an appropriate polymer prodrug. In this work, poly(NIPA)-b-poly(HMNPPA)-b-poly(PEGMA-stat-BA) was synthesized using reversible addition fragmentation chain transfer polymerization and Chlorambucil (Cbl), an anticancer drug, was conjugated to the copolymer via 3-(3-(hydroxymethyl)-4-nitrophenoxy)propyl acrylate (HMNPPA) units to prepare the prodrug. A few biotin acrylate (BA) units were also incorporated to bring potential targeting capability to the prodrug in the copolymer. This polymer prodrug formed spherical micellar nanoparticles in physiological conditions, which were characterized by dynamic light scattering and transmission electron microscopy measurements. The very low critical aggregation concentration (cac) (0.011 mg/mL) of the prodrug, as measured from Nile Red fluorescence, makes it stable against dilution. The polymer prodrug was shown to release Cbl on photoirradiation by soft UV (λ ≥ 365 nm) and laser (λ = 405 nm) light. The prodrug micellar nanoparticles were capable of encapsulating a second drug (doxorubicin, DOX) in their hydrophobic core. On photoirradiation with UV and laser light of the DOX-loaded nanoparticles, both Cbl and DOX were released. Lightinduced breaking of photolabile ester bond resulted in the release of Cbl and caused disruption of the nanoparticles facilitating release of DOX. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay confirmed the nontoxicity of the polymers and effectiveness of the dual drug-loaded micellar nanoparticles toward cancer cells. Confocal microscopy results showed a better cellular internalization capability of the DOX-loaded nanoparticles in cancer cells, possibly due to the presence of cancer cell targeting biotin molecules in the polymer. This new photoresponsive potentially biocompatible and cancer cell-targeted polymer prodrug may be useful for delivery of single and/or multiple hydrophobic drugs.
Journal of Controlled Release, 2001
There are now at least seven polymer-drug conjugates that have entered phase I / II clinical trial as anticancer agents. These include N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1, FCE28068), HPMA copolymer-paclitaxel (PNU 166945), HPMA copolymer-camptothecin, PEG-camptothecin, polyglutamic acid-paclitaxel, an HPMA copolymer-platinate (AP5280) and also an HPMA copolymer-doxorubicin conjugate bearing additionally galactosamine (PK2, FCE28069). The galactosamine is used as a means to target the conjugate to liver for the treatment of primary and secondary liver cancer. Promising early clinical results with lysosomotropic conjugates has stimulated significant interest in this field. Ongoing research is developing (1) conjugates containing drugs that could otherwise not progress due to poor solubility or uncontrollable toxicity; (2) conjugates of agents directed against novel targets; and (3) two-step combinations such as polymer-directed enzyme prodrug therapy (PDEPT) and polymer-enzyme liposome therapy (PELT) that can cause explosive liberation of drug from either polymeric prodrugs or liposomes within the tumour interstitium. Moreover, bioresponsive polymer-based constructs able to promote endosomal escape and thus intracytoplasmic delivery of macromolecular drugs (peptides, proteins and oligonucleotides) are also under study.
Modular Assembly of Reversible Multivalent Targeting Drug Conjugates
Angewandte Chemie (International ed. in English), 2017
Here is described a new modular platform to construct cancer cell targeting drug conjugates. Tripodal boronate complexes, featuring reversible covalent bonds, were design to accommodate, a cytotoxic drug (bortezomib), polyethylene glycol (Peg) chains and folate targeting units. The B-complex core was assembled in one step, and proved stable in different biocompatible conditions, namely human plasma (half-life up to 60 h) and reversible in the presence of glutathione (GSH). The stimulus responsive intracellular cargo delivery was confirmed by confocal fluorescence microscopy and a mechanism for GSH induced B-complex hydrolysis was proposed based on mass spectrometry and DFT calculations. This platform enabled the modular construction of multivalent conjugates exhibiting high selectivity for folate positive MDA-MB-231 cancer cells and IC50's in the nanomolar range.