RESUMO
Immune checkpoint blockade reaches remarkable clinical responses. However, even in the most favorable cases, half of these patients do not benefit from these therapies in the long term. It is hypothesized that the activation of host immunity by co-delivering peptide antigens, adjuvants, and regulators of the transforming growth factor (TGF)-ß expression using a polyoxazoline (POx)-poly(lactic-co-glycolic) acid (PLGA) nanovaccine, while modulating the tumor-associated macrophages (TAM) function within the tumor microenvironment (TME) and blocking the anti-programmed cell death protein 1 (PD-1) can constitute an alternative approach for cancer immunotherapy. POx-Mannose (Man) nanovaccines generate antigen-specific T-cell responses that control tumor growth to a higher extent than poly(ethylene glycol) (PEG)-Man nanovaccines. This anti-tumor effect induced by the POx-Man nanovaccines is mediated by a CD8+ -T cell-dependent mechanism, in contrast to the PEG-Man nanovaccines. POx-Man nanovaccine combines with pexidartinib, a modulator of the TAM function, restricts the MC38 tumor growth, and synergizes with PD-1 blockade, controlling MC38 and CT26 tumor growth and survival. This data is further validated in the highly aggressive and poorly immunogenic B16F10 melanoma mouse model. Therefore, the synergistic anti-tumor effect induced by the combination of nanovaccines with the inhibition of both TAM- and PD-1-inducing immunosuppression, holds great potential for improving immunotherapy outcomes in solid cancer patients.
Assuntos
Melanoma , Macrófagos Associados a Tumor , Camundongos , Animais , Linhagem Celular Tumoral , Imunoterapia , Linfócitos T CD8-Positivos , Microambiente TumoralRESUMO
Poly(2-oxazoline)s (POx) bottle-brush brushes have excellent biocompatible and lubricious properties, which are promising for the functionalization of surfaces for biomedical devices. Herein, a facile synthesis of POx is reported which is based bottle-brush brushes (BBBs) on solid substrates. Initially, backbone brushes of poly(2-isopropenyl-2-oxazoline) (PIPOx) were fabricated via surface initiated Cu0 plate-mediated controlled radical polymerization (SI-Cu0 CRP). Poly(2-methyl-2-oxazoline) (PMeOx) side chains were subsequently grafted from the PIPOx backbone via living cationic ring opening polymerization (LCROP), which result in ≈100 % increase in brush thickness (from 58 to 110â nm). The resultant BBBs shows tunable thickness up to 300â nm and high grafting density (σ) with 0.42â chains nm-2 . The synthetic procedure of POx BBBs can be further simplified by using SI-Cu0 CRP with POx molecular brush as macromonomer (Mn =536â g mol-1 , PDI=1.10), which results in BBBs surface up to 60â nm with well-defined molecular structure. Both procedures are significantly superior to the state-of-art approaches for the synthesis of POx BBBs, which are promising to design bio-functional surfaces.
Assuntos
Materiais Biocompatíveis/síntese química , Oxazóis/síntese química , Cobre/química , Estrutura Molecular , Oxazóis/química , Poliaminas/química , Polimerização , Polipropilenos/químicaRESUMO
Poly(2-oxazoline)s have been investigated for decades as biomaterials. Pioneering early work suggested that hydrophilic poly(2-oxazoline)s are comparable to poly(ethylene glycol) regarding their potential as biomaterials, but the ready commercial availability of the latter has led to its meteoric rise to become the gold standard of hydrophilic synthetic biomaterials. In contrast, poly(2-oxazoline)s almost fell into oblivion. However, in the last decade, this family of polymers has gained much more interest in general and as biomaterials in particular. The rich chemistry and comparably straightforward synthesis of poly(2-oxazoline)s gives many opportunities for tailoring the properties of the resulting biomaterials, allowing the chemist to explore new conjugation chemistry, and to fine-tune the molar mass, hydrophilic-lipophilic balance as well as architecture. Thus, the wide range of demands for various applications of biomaterials can be suitably addressed. This review aims to give a comprehensive and critical update of the development of poly(2-oxazoline) based biomaterials, focusing on the last 5 years, which have seen an explosive increase of interest. We believe that the research regarding this diverse family of polymers will remain strong and will keep growing, in particular after the promising first-in-human studies of a poly(2-oxazoline) drug conjugate. This review aims at researchers and students new to this polymer family and seasoned poly(2-oxazoline) experts alike and attempts to showcase how the chemical diversity of poly(2-oxazoline)s allows a relatively facile and broad access to biomaterials of all kinds.
Assuntos
Materiais Biocompatíveis/química , Oxazóis/química , Animais , Sistemas de Liberação de Medicamentos , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Imunomodulação/efeitos dos fármacos , Oxazóis/imunologia , Oxazóis/toxicidade , Distribuição Tecidual/efeitos dos fármacosRESUMO
Patterned polypeptoid brushes on gold and oxide substrates are synthesized by surface-initiated polymerization of N-substituted glycine N-carboxyanhydrides. Their biofouling resistance is shown by protein and cell adhesion experiments. The accessibility of the system to common patterning protocols is demonstrated by UV-lithography and a µCP approach. Moreover, the terminal secondary amine group of the polypeptoid brushes is functionalized with different fluorescent dyes to demonstrate their chemical accessibility.