RESUMO
The tumor-associated macrophages (TAMs) in intratumoral hypoxic regions are key drivers of immune escape. Reprogramming the hypoxic TAMs to antitumor phenotype holds great therapeutic benefits but remains challenging for current drugs. Here, an in situ activated nanoglycocluster is reported to realize effective tumor penetration and potent repolarization of hypoxic TAMs. Triggered by the hypoxia-upregulated matrix metalloproteinase-2 (MMP-2), the nanoglycocluster is self-assembled from the administered mannose-containing precursor glycopeptides and presents densely-arrayed mannoses to multivalently engage with mannose receptors on M2-like TAMs for efficient phenotype switch. By virtue of the high diffusivity of precursor glycopeptides due to their low molecular mass and weak affinity with TAMs in perivascular regions, the nanoglycoclusters are capable of substantially accumulating in hypoxic areas to strongly interact with local TAMs. This enables the efficient repolarization of overall TAMs with a higher rate than the small-molecule drug R848 and CD40 antibody, and beneficial therapeutic effects in mouse tumor models especially when combining with PD-1 antibody. This on-demand activated immunoagent is endowed with tumor-penetrating properties and inspires the design of diverse intelligent nanomedicines for hypoxia-related cancer immunotherapy.
Assuntos
Neoplasias , Macrófagos Associados a Tumor , Animais , Camundongos , Metaloproteinase 2 da Matriz , Macrófagos , Imunoterapia , Neoplasias/terapia , Neoplasias/patologia , Hipóxia , Glicopeptídeos/farmacologia , Microambiente TumoralRESUMO
Targeted immunomodulation through biomolecule-based nanostructures, especially to dendritic cells (DCs), holds great promise for effective cancer therapy. However, construction of high-performance agonist by mimicking natural ligand to activate immune cell signaling is a great challenge so far. Here, a peptide-based nanoagonist toward CD40 (PVA-CD40) with preorganized interfacial topological structure that activates lymph node DCs efficiently and persistently, achieving amplified immune therapeutic efficacy is described. The on-site fabrication of PVA-CD40 is realized through the click conjugation of two functional peptides including the "CD40 anchoring arm" and the "assembly-driving motor." The resultant polyvalent interface rapidly triggers the receptor oligomerization and downstream signaling. Strikingly, one shot administration of PVA-CD40 elicits maturation period of DCs up to 2.3-fold comparing to that of CD40 antibody. Finally, combining the PVA-CD40 with anti-PD-1 antibody results in subsequent inhibition of tumor growth in both B16F10 and 4T1 mice tumor models with survival rate up to 37%, while none of the mice survives in the clinically relevant CD40 mAb and anti-PD-1 combination-treated group. It is envisioned that the fabrication of antibody-like superstructures in vivo provides an efficient platform for modulating the duration of immune response to achieve optimal therapeutic efficacy.
Assuntos
Células Dendríticas , Neoplasias , Animais , Antígenos CD40 , Imunoterapia/métodos , Camundongos , Neoplasias/tratamento farmacológico , Peptídeos/farmacologiaRESUMO
Due to intrinsic and acquired chemo/radiotherapy-resistance, renal cell carcinoma shows limited therapeutic response to clinically utilized targeting drugs. Here a tumor-activated oncolytic peptide nanomachine is devised to selectively lysing tumor cell membrane without causing drug resistance. Specifically, in the acidic tumor microenvironment, the oncolytic peptide nanomachine automatically activated through morphologically transformation from nanoparticles to nanofibrils with restoring α-helical conformation, which physically bind to tumor cell membrane with multiple (spatially correlated and time-resolved) interactions and subsequently lyse local cell membrane. The IC50 of the oncolytic peptide nanomachine is as low as 2.44 µM and it inhibit up to 90% of tumor cells within 2 h with unique bystander killing effect. In vivo, the tumor inhibition rate of the oncolytic peptide nanomachine is 71% without off-target activity and hemolytic activity. These results support that tumor-selective oncolytic peptide nanomachine represent a promising alternative approach for multidrug-resistant tumor treatments by inducing cell membrane lysis.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Terapia Viral Oncolítica , Vírus Oncolíticos , Carcinoma de Células Renais/terapia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Renais/terapia , Masculino , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/fisiologia , Peptídeos/química , Microambiente TumoralRESUMO
Cancer immunotherapy, leveraging the host's coordinated immune system to fight against tumor has been clinically validated. However, the modest response owing to the multiple ways of tumor immune evasion is one of the challenges in cancer immunotherapy. Tumor associated macrophages (TAMs), as a major component of the leukocytes infiltrating in all tumors, play crucial roles in driving cancer initiation, progress and metastasis via multiple mechanisms such as mediating chronic inï¬ammation, promoting angiogenesis, taming protective immune responses, and supporting migration and intravasation. TAMs targeted therapeutics have achieved remarkable successes in clinical trials mostly through the use of small-molecule agents and antibodies. However, efforts for further application have met with challenges of limited efficacy and safety. Nanomaterials can provide versatile approaches to realize the superior spatiotemporal control over immunomodulation to amplify immune responses, ultimately enhancing the therapeutic benefits and reducing toxicity. Here, the potential drugs used in TAM-centered cancer treatment in clinic are summarized and the recent advances of TAMs targeted nanomedicines in this filed are highlighted. More importantly, we focus on how nanomedicine can exert their advantages in spatial and temporal control of immunomodulation.