Polymer nanomedicines are very attractive to improve the delivery of chemotherapeutics. Polymer conjugates and other polymer‐based nanocarriers allow to increase plasma half‐life and drug ...bioavailability and can also be guided toward tumors using passive and active targeting strategies. Since many chemotherapeutics act on targets that are located in well‐defined subcellular compartments, other important factors that contribute to an efficient therapy include cellular internalization and subsequent intracellular trafficking of the polymer nanomedicines and/or its payload to the appropriate organelle in the cytoplasm. This article provides an overview of the different approaches that have been developed to control intracellular delivery of polymer nanomedicines and discusses the different techniques that can be used to monitor these processes.
Control over the intracellular delivery of drugs is crucial for their therapeutic efficiency. This article presents the approaches that have been developed to control delivery of polymer nanomedicines to specific subcellular compartments (the cytoplasm, the mitochondria, the Golgi apparatus, the endoplasmic reticulum, the nucleus) as well as the methods that have been used to monitor these processes.
Harnessing metal‐free photoinduced reversible‐deactivation radical polymerization (photo‐RDRP) in organic and aqueous phases, we report a synthetic approach to enzyme‐responsive and pro‐apoptotic ...peptide brush polymers. Thermolysin‐responsive peptide‐based polymeric amphiphiles assembled into spherical micellar nanoparticles that undergo a morphology transition to worm‐like micelles upon enzyme‐triggered cleavage of coronal peptide sidechains. Moreover, pro‐apoptotic polypeptide brushes show enhanced cell uptake over individual peptide chains of the same sequence, resulting in a significant increase in cytotoxicity to cancer cells. Critically, increased grafting density of pro‐apoptotic peptides on brush polymers correlates with increased uptake efficiency and concurrently, cytotoxicity. The mild synthetic conditions afforded by photo‐RDRP, make it possible to access well‐defined peptide‐based polymer bioconjugate structures with tunable bioactivity.
Empowered by light: Photoinduced reversible deactivation radical polymerization (photo‐RDRP) enabled access to a new class of bioactive peptide brush polymers. Those peptide‐based brush polymers exhibited well‐defined structures and tunable bioactivities, highlighting their immense potential in biomedical applications.
Human hair is naturally colored by melanin pigments, which afford myriad colors from black, to brown, to red depending on the chemical structures and specific blends. In recent decades, synthetic ...efforts have centered on dopamine oxidation to polydopamine, an effective eumelanin similar to the one found in humans. To date, only a few attempts at polydopamine deposition on human hair have been reported, and their translation to widespread usage and potential commercialization is still hampered by the harsh conditions employed. We reasoned that novel, mild, biocompatible approaches could be developed to establish a metal-free route to tunable, nature-inspired, long-lasting coloration of human hair. Herein, we describe synthetic and formulation routes to achieving this goal and show efficacy on a variety of human hair samples via multiple spectroscopic and imaging techniques. Owing to the mild and inexpensive conditions employed, this novel approach has the potential to replace classical harsh hair dyeing conditions that have raised concerns for several decades due to their potential toxicity.
In this Minireview, we describe synthetic polymers densely functionalized with sequence‐defined biomolecular sidechains. We focus on synthetic brush polymers of oligonucleotides, oligosaccharides, ...and oligopeptides, prepared via graft‐through polymerization from biomolecule functionalized monomers. The resulting structures are brush polymers wherein a biomolecular graft is positioned at each monomer backbone unit. We describe key synthetic milestones, identify synthetic opportunities, and highlight recent advances in the field, including biological applications.
Biomolecular brush polymers are a unique class of materials. In this Minireview, we examine three families of biomolecular brush polymers with different side chains: 1) oligonucleotides, 2) oligosaccharides, and 3) oligopeptides. These materials display distinctive characteristics such as increased cell‐uptake, resistance to enzymes and bioavailability compared to the biomolecular oligomers on their own as individual sequences.
Chain-end-labeled polymers are interesting for a range of applications. In polymer nanomedicine, chain-end-labeled polymers are useful to study and help understand cellular internalization and ...intracellular trafficking processes. The recent advent of fluorescent label-free techniques, such as nanoscale secondary ion mass spectrometry (NanoSIMS), provides access to high-resolution intracellular mapping that can complement information obtained using fluorescent-labeled materials and confocal microscopy and flow cytometry. Using poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA) as a prototypical polymer nanomedicine, this paper presents a synthetic strategy to polymers that contain trace element labels, such as fluorine, which can be used for NanoSIMS analysis. The strategy presented in this paper is based on reversible addition fragmentation chain transfer (RAFT) polymerization of pentafluorophenyl methacrylate (PFMA) mediated by two novel chain-transfer agents (CTAs), which contain either one (α) or two (α,ω) fluorine labels. In the first part of this study, via a number of polymerization experiments, the polymerization properties of the fluorinated RAFT CTAs were established. 19F NMR spectroscopy revealed that these fluorinated RAFT agents possess unique spectral signatures, which allow to directly monitor RAFT agent conversion and measure end-group fidelity. Comparison with 4-cyanopentanoic acid dithiobenzoate, which is a standard CTA for the RAFT polymerization of PFMA, revealed that the introduction of one or two fluorine labels does not significantly affect the polymerization properties of the CTA. In the last part of this paper, a proof-of-concept study is presented that demonstrates the feasibility of the fluorine-labeled poly(pentafluorophenyl methacrylate) polymers as platforms for the postpolymerization modification to generate PHPMA-based polymer nanomedicines.
Recent advances in polymer chemistry, materials sciences, and biotechnology have allowed the preclinical development of sophisticated programmable nanomedicines and materials that are able to ...precisely respond to specific disease‐associated triggers and microenvironments. These stimuli, endogenous to the targeted diseases, include pH, redox‐state, small molecules, and protein upregulation. Herein, recent advances and innovative approaches in programmable soft materials capable of sensing the aforementioned disease‐associated stimuli and responding via a range of dynamic processes including morphological and size transitions, changes in mobility and retention, as well as disassembly are described. In this field generally, the majority of ongoing and past research effort has focused on oncology. Given this interest, examples of the latest innovative approaches to chemo‐ and immunotherapy treatment strategies for cancer are presented. Moreover, as the field broadens its attention, applications of programmable materials in other diseases are highlighted, with a special focus on cardiovascular disease and diabetes mellitus, where limited attention is paid by the field, but where many promising avenues exist with high potential impact.
Over the past decade, the field of programmable soft materials for biomedical applications has rapidly expanded. Recent advances that show promising results in preclinical animal models are described for the treatment of cancer, cardiovascular disease, and diabetes. Efforts have focused on materials capable of sensing disease‐associated endogenous stimuli and responding via a range of dynamic processes.
Inhibition of P-glycoprotein (P-gp) transporter is an attractive approach for the reversion of cancer-associated multidrug resistance (MDR). Poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA)-based ...carriers that are able to release the anticancer drug doxorubicin in the lysosomes have shown promise to reduce P-gp mediated resistance. This is attributed to the release of the drug in close proximity to the nucleus and distant from the P-gp transporter. This work presents a strategy to maximize P-gp inhibition and enhance doxorubicin cytotoxicity in cancer cells by using a dual functional PHPMA conjugate carrying both the anticancer drug doxorubicin and the P-glycoprotein inhibitor zosuquidar (Zos). While doxorubicin was connected to the polymer backbone via a lysosomally cleavable spacer, the P-gp inhibitor Zos was attached by a hydrazone linker in order to promote release in the early stage of the endocytic process and maximize its cytosolic concentration in proximity of the P-gp transporter. Following Zos modification and determination of its ability to inhibit P-gp, conjugation to the PHPMA polymer backbone resulted in enhanced doxorubicin cytotoxicity in resistant A2780ADR ovarian carcinoma cells. Finally, the incorporation of both Dox and Zos in a single polymer carrier enhanced P-gp inhibition as compared to a control PHPMA conjugate containing only Dox.
Mussel Adhesive-Inspired Proteomimetic Polymer Berger, Or; Battistella, Claudia; Chen, Yusu ...
Journal of the American Chemical Society,
03/2022, Volume:
144, Issue:
10
Journal Article
Peer reviewed
Herein, a synthetic polymer proteomimetic is described that reconstitutes the key structural elements and function of mussel adhesive protein. The proteomimetic was prepared via graft-through ...ring-opening metathesis polymerization of a norbornenyl-peptide monomer. The peptide was derived from the natural underwater glue produced by marine mussels that is composed of a highly repetitive 10 amino acid tandem repeat sequence. The hypothesis was that recapitulation of the repeating unit in this manner would provide a facile route to a nature-inspired adhesive. To this end, the material, in which the arrangement of peptide units was as side chains on a brush polymer rather than in a linear fashion as in the natural protein, was examined and compared to the native protein. Mechanical measurements of adhesion forces between solid surfaces revealed improved adhesion properties over the natural protein, making this strategy attractive for diverse applications. One such application is demonstrated, using the polymers as a surface adhesive for the immobilization of live cells.
BACKGROUND AND OBJECTIVESTo determine the incidence of signs and symptoms of temporomandibular disorder in elective surgery patients who underwent orotracheal intubation.METHODSThis was a ...longitudinal controlled study with two groups. The study group included patients who underwent orotracheal intubation and a control group. We used the American Academy of Orofacial Pain questionnaire to assess the temporomandibular disorder signs and symptoms one-day postoperatively (T1), and the patients' baseline status prior to surgery (T0) was also recorded. The same questionnaire was used after three months (T2). The mouth opening amplitude was measured at T1 and T2. We considered a p value of less than 0.05 to be significant.RESULTSWe included 71 patients, with 38 in the study group and 33 in the control. There was no significant difference between the groups in age (study group: 66 52.5-72; control group: 54 47-68; p=0.117) or in their belonging to the female gender (study group: 57.9%; control group: 63.6%; p=0.621). At T1, there were no statistically significant differences between the groups in the incidence of mouth opening limitation (study group: 23.7% vs.CONTROL GROUP18.2%; p=0.570) or in the mouth opening amplitude (study group: 45 40-47 vs.CONTROL GROUP46 40-51; p=0.278). At T2 we obtained similar findings. There was no significant difference in the affirmative response to all the individual questions in the American Academy of Orofacial Pain questionnaire.CONCLUSIONSIn our population, the incidence of signs and symptoms of temporomandibular disorder of muscular origin was not different between the groups.
Polymeric nanoscale materials able to target and accumulate in the tumor microenvironment (TME) offer promising routes for a safer delivery of anticancer drugs. By reaching their targets before ...significant amounts of drug are released, such materials can reduce off-target side effects and maximize drug concentration in the TME. However, poor drug loading capacity and inefficient nanomaterial penetration into the tumor can limit their therapeutic efficacy. Herein, we provide a novel approach to achieve high loading profiles while ensuring fast and efficient drug penetration in the tumor. This is achieved by co-polymerizing light-sensitive paclitaxel with monomers responsive to tumor-associated enzymes, and assembling the resulting di-block copolymers into spherical micelles. While light exposure enables paclitaxel to decouple from the polymeric backbone into light-activated micelles, enzymatic digestion in the TME initiates its burst release. Through a series of in vitro cytotoxicity assays, we demonstrate that these light-switch micelles hold greater potency than covalently linked, non-triggered micelles, and enable therapeutic profiles comparable to that of the free drug.
PDF
