Amphiphilic tri- and tetra-block co-polymers combining versatile functionality with facile assembly into cytocompatible nanoparticles

Vasey, Catherine E.; Pearce, Amanda K.; Sodano, Federica; Cavanagh, Robert; Abelha, Thais Fedatto; Crucitti, Valentina Cuzzucoli; Anane-Adjei, Akosua B.; Ashford, Marianne; Gellert, Paul; Taresco, Vincenzo; Alexander, Cameron

doi:10.1039/c9bm00667b

Cited by 21 publications

(39 citation statements)

References 52 publications

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“…The surface charge of the nanoparticles was negative, below ‐10 mV, due to the presence of the hydrophilic PEGMA corona shell. This provided confirmation of the stability of the BOC‐protected functionality within the nanoparticle core, facilitating the on‐demand deprotection and functionalization for further applications that we have previously demonstrated . A final consideration for nanoparticles intended for drug delivery applications is their biodegradation and ultimate in vivo fate.…”

Section: Resultssupporting

confidence: 56%

“…The desired amounts of LA and initiators (HEMA or PEGMA) were weighed into a vial (predried in an oven at 100 °C overnight) . The [M]:[I] was kept in the range of 5–10:1.…”

Section: Methodsmentioning

confidence: 99%

“…A quantity of the chosen monomer, HEMA‐(LA) 10 , HEMA‐(LA) 10 ‐(tBSC) 10 , and HEA‐(LA) 15 ‐(tBSC) 15 (15 mg) were dissolved in 30 µL of DMSO‐ d 6 in a vial . 2,2‐dimethyl‐2‐phenyl acetophenone (DMPA) (25 µL aliquot of a 40 mg mL −1 solution in DMSO‐ d 6 ) and benzyl mercaptan (5 eq.)…”

Section: Methodsmentioning

confidence: 99%

“…Versatility can be introduced to the polyesters through either copolymerization with functionalizable monomers, or through adopting functional initiators. The former can be achieved utilizing cyclic carbonates, which can provide pendant side‐chain functionality (such as tert‐butyloxycarbonyl (BOC)‐protected amines), and the latter includes the use of (meth)acrylates to provide an end‐chain reactive double bond . Ideally, a combination of the two approaches can result in the flexibility to synthesize a wide range of possible polymeric functionalities and structures which can undergo further reactions post‐polymerization …”

Section: Introductionmentioning

confidence: 99%

“…In this regard, we have previously demonstrated the use of triazabicyclodecene (TBD) and 1,8‐diazabicyclo[5.4.0]undec‐5‐ene (DBU) as organocatalysts for the synthesis of PEG and HEMA‐initiated polyesters and polycarbonates, demonstrating good control over the final polymer architectures when employing optimised reaction conditions . However, despite the high catalytic activity of TBD, when low molecular weight materials (<2500 Da) were targeted, the kinetics of transesterification prevailed over the ROP process, limiting the synthetic strategy toward accessing oligomeric species .…”

Section: Introductionmentioning

confidence: 99%

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Versatile, Highly Controlled Synthesis of Hybrid (Meth)acrylate–Polyester–Carbonates and their Exploitation in Tandem Post‐Polymerization–Functionalization

Pearce

Vasey

Anane-Adjei

et al. 2019

Macro Chemistry & Physics

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The use of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) as a mild catalyst for the ring‐opening polymerization (ROP) of the pharma‐friendly and biodegradable monomer lactide and a functionalizable tert‐butyloxycarbonyl (BOC)‐protected cyclic carbonate is explored. Successful and controlled ROP is demonstrated when employing a series of labile‐ester (bis)(meth)acrylate initiators to produce macromonomers suitable for a range of post‐polymerization modifications. Importantly, the use of DBU ensured retention of the BOC group of the carbonate monomer during the polymerization, thus facilitating the production of highly functionalizable hybrid materials unobtainable using the more reactive triazabicyclodecene (TBD). Subsequently, a variety of short homo‐ and copolymers are synthesized with good control over material properties and final polymer composition. Successful attainment of these short copolymers confirm that DBU can overcome the previously observed limitations of TBD related to its kinetic competition between ROP and transesterification side‐reactions under these reaction conditions. Furthermore, the fidelity of the hydroxyl and (meth)acrylic end groups are maintained as confirmed by a series of secondary tandem reactions. The macromonomers are also utilized in reversible addition−fragmentation chain‐transfer polymerization (RAFT) polymerization for the production of amphiphilic block or random copolymers with a hydrophilic comonomer, poly(ethyleneglycol)methacrylate. The amphiphilic copolymers produced via the tandem RAFT reaction demonstrate the ability to self‐assemble into monodisperse nanoparticles in aqueous environments.

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Section: Resultssupporting

confidence: 56%

“…The desired amounts of LA and initiators (HEMA or PEGMA) were weighed into a vial (predried in an oven at 100 °C overnight) . The [M]:[I] was kept in the range of 5–10:1.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Versatile, Highly Controlled Synthesis of Hybrid (Meth)acrylate–Polyester–Carbonates and their Exploitation in Tandem Post‐Polymerization–Functionalization

Pearce

Vasey

Anane-Adjei

et al. 2019

Macro Chemistry & Physics

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Functionalized Block Co‐Polymer Pro‐Drug Nanoparticles with Anti‐Cancer Efficacy in 3D Spheroids and in an Orthotopic Triple Negative Breast Cancer Model

Taresco

Abelha

Cavanagh

et al. 2020

Advanced Therapeutics

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Amphiphilic block co-polymers composed of poly(ethylene glycol)-co-poly(lactide)-co-poly(2-((tert-butoxycarbonyl)amino)-3-propyl carbonate) (PEG-pLA-pTBPC) are synthesized in monomer ratios and arrangements to enable assembly into nanoparticles with different sizes and architectures. These materials are based on components in clinical use, or known to be biodegradable, and retain the same fundamental chemistry across "AB" and "BAB" block architectures. In MCF7 and MDA-MB-231 breast cancer cells, nanoparticles of <100 nm are internalized most rapidly, by both clathrin-and caveolin-mediated pathways. In THP-1 cells, polymer architecture and length of the hydrophilic block is the most important factor in the rate of internalization. The organ distributions of systemically injected nanoparticles in healthy mice indicate highest accumulation of the BAB-blocks in lungs and liver and the lowest accumulation in these organs of a methoxyPEG 5000-pLA-pTBPC polymer. Conjugation of doxorubicin via a serum-stable urea linker to the carbonate regions of PEG 5000-pLA-pTBPC generates self-assembling nanoparticles which are more cytotoxic in 2D, and penetrate further in 3D spheroids of triple negative breast cancer cells, than the free drug. In an aggressive orthotopic triple negative breast cancer mouse model, the methoxyPEG 5000-pLA-pTBPC is of similar potency to free doxorubicin but with no evidence of adverse effects in terms of body weight.

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Antimicrobial Hyperbranched Polymer–Usnic Acid Complexes through a Combined ROP‐RAFT Strategy

Rauschenbach

Lawrenson

Taresco

et al. 2020

Macromol. Rapid Commun.

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Polymer–drug conjugates have received considerable attention over the last decades due to their potential for improving the clinical outcomes for a range of diseases. It is of importance to develop methods for their preparation that have simple synthesis and purification requirements but maintain high therapeutic efficacy and utilize macromolecules that can be cleared via natural excretory pathways upon breakdown. Herein, the combination of ring‐opening polymerization (ROP) and reversible addition−fragmentation chain‐transfer (RAFT) polymerization is described for the straightforward synthesis of amphiphilic, stimuli‐responsive, biodegradable, and highly functionalizable hyperbranched polymers. These unimolecular nanoparticles demonstrate a versatile platform for the synthesis of polymer–drug conjugates owing to the inclusion of a Boc‐protected polycarbonate moiety in either a block or random copolymer formation. A proof‐of‐concept study on the complexation of the poorly water‐soluble antimicrobial drug usnic acid results in polymer‐drug complexes with powerful antimicrobial properties against gram‐positive bacteria. Therefore, this work highlights the potential of amphiphilic and biodegradable hyperbranched polymers for antimicrobial applications.

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Amphiphilic tri- and tetra-block co-polymers combining versatile functionality with facile assembly into cytocompatible nanoparticles

Abstract: Control in ROP allows polymers to be synthesized with a wide range of architectures and self-assembly properties.

Cited by 21 publications

References 52 publications

Versatile, Highly Controlled Synthesis of Hybrid (Meth)acrylate–Polyester–Carbonates and their Exploitation in Tandem Post‐Polymerization–Functionalization

Versatile, Highly Controlled Synthesis of Hybrid (Meth)acrylate–Polyester–Carbonates and their Exploitation in Tandem Post‐Polymerization–Functionalization

Functionalized Block Co‐Polymer Pro‐Drug Nanoparticles with Anti‐Cancer Efficacy in 3D Spheroids and in an Orthotopic Triple Negative Breast Cancer Model

Antimicrobial Hyperbranched Polymer–Usnic Acid Complexes through a Combined ROP‐RAFT Strategy

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