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Photothermal immunotherapy of melanoma using TLR-7 agonist laden tobacco mosaic virus with polydopamine coat.

ABSTRACT: Photothermal therapy (PTT) is a promising cancer treatment that debulks tumors locally while priming immune responses. However, PTT as a standalone treatment approach often has limited systemic efficacy, motivating the development of synergistic combination approaches. Toward this goal, herein, the tobacco mosaic virus (TMV) was loaded with a small molecule immunomodulator, toll-like receptor 7 agonist (1V209), and its surface was coated with photothermal biopolymer polydopamine (PDA). The resulting 1V209-laden and PDA-coated TMV was used to treat B16F10 dermal melanoma in C57BL/6 mice. 1V209-TMV-PDA was intratumorally injected and irradiated using an 808-nm near infrared laser. 60 % of the mice receiving PTT with intratumoral 1V209-TMV-PDA + laser remained alive at the end point - in contrast to only 20 % survivors were observed in the control group. Immunological analysis indicates systemic anti-tumor immunity being induced by the combination therapy with a greater number of tumor-specific T cells (as determined by a splenocyte assay). This study highlights the potential of TMV versatility as a multifunctional nano-platform for combined PTT-immunotherapy.

SUBMITTER: Nkanga CI

PROVIDER: S-EPMC10530638 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Photothermal immunotherapy of melanoma using TLR-7 agonist laden tobacco mosaic virus with polydopamine coat.

Nkanga Christian Isalomboto CI Ortega-Rivera Oscar A OA Steinmetz Nicole F NF

Nanomedicine : nanotechnology, biology, and medicine 20220618

Photothermal therapy (PTT) is a promising cancer treatment that debulks tumors locally while priming immune responses. However, PTT as a standalone treatment approach often has limited systemic efficacy, motivating the development of synergistic combination approaches. Toward this goal, herein, the tobacco mosaic virus (TMV) was loaded with a small molecule immunomodulator, toll-like receptor 7 agonist (1V209), and its surface was coated with photothermal biopolymer polydopamine (PDA). The resul ...[more]

PMID: 35728739

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Project description:Photothermal therapy (PTT) can be an effective antitumor therapy, but it may not completely eliminate tumor cells, leading to the risk of recurrence or metastasis. Here we describe nanocarriers that allow combination therapy involving PTT and immunotherapy. Nanocarriers are prepared by coating Al2O3 nanoparticles with non-toxic, biodegradable polydopamine, which shows high photothermal efficiency. A near-infrared laser irradiation can kill the majority of tumor tissues, resulting in the release of tumor-associated antigens. The Al2O3 within the nanoparticles, together with CpG, acts as an adjuvant to trigger robust cell-mediated immune responses that can help eliminate the residual tumor cells and reduce the risk of tumor recurrence. Methods: The characteristics and photothermal performance of polydopamine-coated Al2O3 nanoparticles were examined after one-step preparation. Then we studied their internalization, photothermal toxicity and immunostimulatory activity in vitro. For in vivo experiments, these nanocarriers were injected directly into B16F10 melanoma allografts in mice to ensure specific localization. After photothermal irradiation on day 0, mice were subcutaneously injected with CpG adjuvant on day 1, 3 and 5. Tumor volumes and number of living mice were recorded every two days. Moreover, various immune responses induced by our combined therapy were tested for mechanism research. Results: 50% of mice after our combined treatment successfully achieved the goal of tumor eradication, and survived for 120 days, which was the end point of the experiment. Mechanism studies demonstrated the combined therapy efficiently led to dendritic cell maturation, resulting in the secretion of antibodies and cytokines as well as the proliferation of splenocytes and lymphocytes for anti-tumor immunotherapy. Conclusion: Taken together, these results demonstrated the promise of our combined photothermal therapy and immunotherapy for tumor shrinkage, which merited further research.

Project description:BackgroundAlthough tobacco mosaic virus (TMV) coat protein (CP) has been isolated from virus particles and its crystals have grown in ammonium sulfate buffers for many years, to date, no one has reported on the crystallization of recombinant TMV-CP connecting peptides expressed in E. coli.MethodsIn the present papers genetically engineered TMV-CP was expressed, into which hexahistidine (His) tags or glutathione-S-transferase (GST) tags were incorporated. Considering that GST-tags are long peptides and His-tags are short peptides, an attempt was made to grow crystals of TMV-CP cleaved GST-tags (WT-TMV-CP32) and TMV-CP incorporated His-tags (WT-His-TMV-CP12) simultaneously in ammonium sulfate buffers and commercial crystallization reagents. It was found that the 20S disk form of WT-TMV-CP32 and WT-His-TMV-CP12 did not form high resolution crystals by using various crystallization buffers and commercial crystallization reagents. Subsequently, a new experimental method was adopted in which a range of truncated TMV-CP was constructed by removing several amino acids from the N- or the C-terminal, and high resolution crystals were grown in ammonium sulfate buffers and commercial crystallization reagents.ResultsThe new crystallization method was developed and 3.0 Å resolution macromolecular crystal was thereby obtained by removing four amino acids at the C-terminal of His-TMV-CP and connecting six His-tags at the N-terminal of His-TMV-CP (TR-His-TMV-CP19). The Four-layer aggregate disk structure of TR-His-TMV-CP19 was solved. This phenomenon showed that peptides at the C-terminus hindered the growth of high resolution crystals and the peptides interactions at the N-terminus were attributed to the quality of TMV-CP crystals.ConclusionA 3.0 Å resolution macromolecular crystal of TR-His-TMV-CP19 was obtained and the corresponding structure was solved by removing four amino acids at the C-terminus of TMV-CP and connecting His-tags at the N-terminus of TMV-CP. It indicated that short peptides influenced the resolution of TMV-CP crystals.

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Photothermal immunotherapy of melanoma using TLR-7 agonist laden tobacco mosaic virus with polydopamine coat.

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Photothermal immunotherapy of melanoma using TLR-7 agonist laden tobacco mosaic virus with polydopamine coat.

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