A Tale of Drug-Carrier Optimization: Controlling Stimuli Sensitivity via Nanoparticle Hydrophobicity through Drug Loading

Lin, Yen‐Nan; Khan, Sarosh; Song, Yue; Dong, Mei; Shen, Yidan; Tran, David K.; Pang, Ching; Zhang, Fuwu; Wooley, Karen L.

doi:10.1021/acs.nanolett.0c02319

Cited by 15 publications

(12 citation statements)

References 72 publications

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“…This might contribute to the formation of large agglomerates, in which DOX in the polymer chain forms a hydrophobic core via intra- and intermolecular hydrophobic interactions under static conditions, as described above. Lin et al recently reported that aqueous accessibility to the hydrophobic drug-loaded moiety would decrease and limit the diffusion of water and water-soluble molecules, which would reduce the responsiveness to stimuli that could prompt the release of drugs . Even though the hydrazone bond would be cleaved under acidic conditions in the system of LP–DOX as well, the diffusion of the released DOX must be suppressed in the restricted space of the hydrophobic core.…”

Section: Resultsmentioning

confidence: 99%

“…Lin et al recently reported that aqueous accessibility to the hydrophobic drug-loaded moiety would decrease and limit the diffusion of water and watersoluble molecules, which would reduce the responsiveness to stimuli that could prompt the release of drugs. 56 Even though the hydrazone bond would be cleaved under acidic conditions in the system of LP−DOX as well, the diffusion of the released DOX must be suppressed in the restricted space of the hydrophobic core. This might also provide an opportunity for the hydrazone bond to re-form between DOX and the polymer chain, resulting in the suppression of the DOX release.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Phosphorylcholine-Grafted Molecular Bottlebrush–Doxorubicin Conjugates: High Structural Stability, Long Circulation in Blood, and Efficient Anticancer Activity

et al. 2020

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Controlling the particle structure of tumor-targeting nanomedicines in vivo remains challenging but must be achieved to control their in vivo fate and functions. Molecular bottlebrushes (MBs), where brush side chains are densely grafted from a main chain, have recently received attention as building blocks of polymer-based prodrugs because their rigid structure would be expected to demonstrate high structural stability in vivo. Here, we synthesized a poly(methacryloyloxyethyl phosphorylcholine) (pMPC)-grafted molecular bottlebrush (PCMB) conjugated with a cancer drug, doxorubicin (DOX), via an acid-cleavable hydrazone bond. A pMPC-based linear polymer (LP) conjugated with DOX was also prepared for comparison. We confirmed the lack of structural transition in the PCMB between before and after conjugation with DOX using small-angle light and X-ray scattering techniques, whereas the structure of LP was significantly influenced by DOX conjugation and transformed from a randomcoil structure to a large agglomerate via hydrophobic interactions among DOXs. Although PCMB−DOX and LP−DOX showed comparable tissue permeability, pharmacokinetics, and ability to accumulate in tumor tissues, the antitumor efficacy of PCMB−DOX was better than that of LP−DOX. This was presumably due to the formation of LP−DOX agglomerates. The diffusion of cleaved DOX would be restricted in the hydrophobic core of the agglomerate, resulting in the DOX release at the tumor site being compromised. In contrast to LP−DOX, DOX release from PCMB−DOX was not compromised after accumulation in tumor tissues because it did not form such an agglomerate, resulting in the strong antitumor effect. We have demonstrated the potential of MBs as building blocks of drug carriers and believe that these findings can contribute to the design of polymer-based nanomedicines.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Phosphorylcholine-Grafted Molecular Bottlebrush–Doxorubicin Conjugates: High Structural Stability, Long Circulation in Blood, and Efficient Anticancer Activity

et al. 2020

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“…Naturally sourced sugar-based polymers are promising alternatives to petroleum-based materials for various functional and structural applications, due to their high abundance, structural diversities, and degradation potential. − To date, organocatalytic ring-opening polymerizations (ROPs) of cyclic carbonate monomers have been demonstrated as low toxic, metal-free, and mild pathways to prepare sugar-based polycarbonates with predeterminable molar masses and narrow dispersities. − However, there are few reports on the regioregularity between sugar monomer repeat units. Buchard and co-workers studied the 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)-catalyzed ROP of six-membered d -mannose-based 4,6-cyclic carbonates .…”

Section: Introductionmentioning

confidence: 99%

Complexities of Regioselective Ring-Opening vs Transcarbonylation-Driven Structural Metamorphosis during Organocatalytic Polymerizations of Five-Membered Cyclic Carbonate Glucose Monomers

Shen

Yang

Song

et al. 2022

JACS Au

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Rigorous investigations of the organobase-catalyzed ring-opening polymerizations (ROPs) of a series of five-membered cyclic carbonate monomers derived from glucose revealed that competing transcarbonylation reactions scrambled the regiochemistries of the polycarbonate backbones. Regioirregular poly(2,3-α- d -glucose carbonate) backbone connectivities were afforded by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)-catalyzed ROPs of three monomers having different cyclic acetal protecting groups through the 4- and 6-positions. Small molecule studies conducted upon isolated unimers and dimers indicated a preference for Cx–O2 vs Cx–O3 bond cleavage from tetrahedral intermediates along the pathways of addition–elimination mechanisms when the reactions were performed at room temperature. Furthermore, treatment of isolated 3-unimer or 2-unimer, having the carbonate linkage in the 3- or 2-position as obtained from either Cx–O2 or Cx–O3 bond cleavage, respectively, gave the same 74:26 (3-unimer:2-unimer) ratio, confirming the occurrence of transcarbonylation reactions with a preference for 3-unimer vs. 2-unimer formation in the presence of organobase catalyst at room temperature. In contrast, unimer preparation at −78 °C favored Cx–O3 bond cleavage to afford a majority of 2-unimer, presumably due to a lack of transcarbonylation side reactions. Computational studies supported the experimental findings, enhancing fundamental understanding of the regiochemistry resulting from the ring-opening and subsequent transcarbonylation reactions during ROP of glucose carbonates. These findings are expected to guide the development of advanced carbohydrate-derived polymer materials by an initial monomer design via side chain acetal protecting groups, with the ability to evolve the properties further through later-stage structural metamorphosis.

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“…These delivery systems are specifically designed to overcome the shortcomings associated with traditional drug delivery mechanisms, including poor biodistribution, high toxicity, and poor sensitivity. 1,2 By using modified magnetic particles as drug carriers and enriching magnetic drug particles in the lesion, the loaded drug is released in a controlled manner to achieve targeted therapy. Thus, the magnetically targeted drug delivery system achieves the four-fold objective of synergism, toxicity reduction, controlled release, and gradual release.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the performance of magnetic targeting drug carriers prepared using two synthesis methods

et al. 2021

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A Tale of Drug-Carrier Optimization: Controlling Stimuli Sensitivity via Nanoparticle Hydrophobicity through Drug Loading

Cited by 15 publications

References 72 publications

Phosphorylcholine-Grafted Molecular Bottlebrush–Doxorubicin Conjugates: High Structural Stability, Long Circulation in Blood, and Efficient Anticancer Activity

Phosphorylcholine-Grafted Molecular Bottlebrush–Doxorubicin Conjugates: High Structural Stability, Long Circulation in Blood, and Efficient Anticancer Activity

Complexities of Regioselective Ring-Opening vs Transcarbonylation-Driven Structural Metamorphosis during Organocatalytic Polymerizations of Five-Membered Cyclic Carbonate Glucose Monomers

Comparison of the performance of magnetic targeting drug carriers prepared using two synthesis methods

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