Nanotechnology synergized immunoengineering for cancer

Abstract

Novel strategies modulating the immune system yielded enhanced anticancer responses and improved cancer survival. Nevertheless, the success rate of immunotherapy in cancer treatment has been below expectation(s) due to unpredictable efficacy and off-target effects from systemic dosing of immunotherapeutic(s). As a result, there is an unmet clinical need for improving conventional immunotherapy. Nanotechnology offers several new strategies, multimodality, and multiplex biological targeting advantage to overcome many of these challenges. These efforts enable programming the pharmacodynamics, pharmacokinetics, and delivery of immunomodulatory agents/co-delivery of compounds to prime at the tumor sites for improved therapeutic benefits. This review provides an overview of the design and clinical principles of biomaterials driven nanotechnology and their potential use in personalized nanomedicines, vaccines, localized tumor modulation, and delivery strategies for cancer immunotherapy. In this review, we also summarize the latest highlights and recent advances in combinatorial therapies availed in the treatment of cold and complicated tumors. It also presents key steps and parameters implemented for clinical success. Finally, we analyse, discuss, and provide clinical perspectives on the integrated opportunities of nanotechnology and immunology to achieve synergistic and durable responses in cancer treatment.

Keywords: Adjuvants; Biomaterials; Cancer treatment; Imaging; Immunotherapy; Nanoparticles; Theranostic; Tumor; Vaccines.

Fig. 1.. Manipulation of T cells, infiltration of immune cells in tumor microenvironment, checkpoint inhibitor, and approaches followed in vaccine development.

Manipulation of T cells includes antigen representation by DC and artificial antigen presenting systems (aAPC), and nucleic acid transfer. The immune cells (macrophages, T cells, dendritic cells) infiltrate in the tumor microenvironment. The approaches for vaccine development include the injection of engineered dendritic cells, antigen, and aAPC.

Fig. 2.. Developmental Pathway and Interconnectivity of Immunotherapy and Nanotechnology:

The top 3 spikes show the current advancements, while the bottom spikes show the advantages and disadvantages of nano-immunotherapy and convention immunotherapy, respectively. Integration of nanotechnology, material science, and nano-immunoimaging towards reinforcing cancer immunotherapy. The area of pie sector represents the percentage of current development. Abbreviation: checkpoint inhibitor (CI), cytokines (CK), drug delivery (DD), localized therapy (LT), microenvironment tunning (MT), cancer vaccines (CV), microenivornment modulation (MM), combination therapy (CT), controlled release (CR), implantable and injectable biomaterials (I&I Biomaterials).

Fig. 3.. Role of nanoparticles in the different areas of cancer immunotherapy.

Nanoparticles are helpful in a) targeted delivery of antigens to dendritic cells, b) controlled and triggered release of antigen and adjuvants to the tumor. c) Conjugation to the T cells for long-term activation and increasing the efficiency of checkpoint blockade therapy.

Fig. 4.

a) Schematic showing the fabrication of the anti-CD3e f(ab′)2 fragments attached poly(β-amino ester) nanoparticles. b) Schematic showing the conjugation of PIGF-2 peptide to IgG antibody for improving the binding to ECM proteins. Adopted with permission from reference [107] (a) and [115] (b)

Fig. 5.

a) Schematic showing the preparation of immunoliposomes. b) Size distribution of immunoliposomes before and after coupling with T cells. c) Quantification of ligand (IL2 or anti-Thy1.1) to the liposomes containing different concentration of maleimide. d) Timeline representing the study regimen. e) Representative bioluminescent images of mice over different time periods. f) Quantitative analysis of whole-body imaging. g) Flow cytometric analysis after the adaptive transfer of the tumor-specific (vβ13 TCR+) T cells. h) Quantitative analysis of tumor-specific (vβ13 TCR+) T cells in the inguinal lymph nodes. Adopted with permission from reference [110].

Fig. 6.

a) Schematic representation of the induced immunotherapy after NIR-PIT. b) General regimen adopted for the NIR-PIT. c) Biflanked tumor model: right tumor was treated with NIR light and anti-CD25-F(ab′)2–IR700 or (ab′)2–IR700 driven phototherapy, while the left tumor was left untreated. d) Representative bioluminescence images showing the changes after the localized NIR-PIT. e) Reduction in the relative light units (RLU) of the right tumor after NIR-PIT as well as in the left non-irradiated tumor. f) Reduction in size of the tumor after the CD25 treated right tumor as well as non-irradiated one. g) Prolonged survival of mice after NIR-PIT. h) Change in weight after the NIR-PIT, i) Edema due to NIR-PIT at both tumors after CD25 targeted NIR-PIT, j) Depletion of CD4+CD25+Foxp3+ Tregs in the right tumor but not in the left untreated. k) Regression of multiple LL/2-luc tumors after the localized CD25 targeted NIR-PIT at the right tumor. l) Negligible effect on the MC38-luc tumor after NIR-PIT on the LL/2-luc tumors of the right side. Adopted with permission from reference [124].

Fig. 7.. Synergistic effect of conventional therapies and immunotherapy in reference to nanoparticles functionalization.

Chemotherapy, photothermal, photodynamic, radiotherapy, and gene therapy cause immunogenic cell death, and nanoparticle functionalization leads to robust activation of the immune response, which is helpful in observing the abscopal effect.

Fig. 8.

a) Schematic of sHDL-DOX synthesis for the chemo-immunotherapy. b) Schematic showing the intratumoral delivery of DOX due to ultra-small nature of sHDL, and also triggering ICD and danger signals like HMGB1 and calreticulin. c) Representative bioluminescence images of mice during the course of study. d) Quantification of the signals. e) Imaging of the major organs harvested. f) Quantification of signals from each organ harvested. g) Survival graph of mice. Adopted from reference [141] which is distributed under a Creative Commons Attribution Noncommercial License 4.0 (CC BY-NC).

Fig. 9.

a) Schematic showing the fabrication of GO(HPPH)-PEG-HK. b.i, ii, iii, iv) Different regimens of GO(HPPH)-PEG-HK driven PDT in the subcutaneous 4T1 tumor model (i), GO(HPPH)-PEG-HK driven PDT at one tumor model to stimulate immunity at the second tumor (ii), GO(HPPH)-PEG-HK driven PDT to induce the necrotic 4T1 cells to use them for tumor vaccination (iii, iv). c,g) Representative bioluminescence images (c), and quantitative analysis (g). d) Representative images of the lung filled with Indian ink. e, f) Quantitative analysis (e) and H&E staining (f) of metastatic lesions in lungs. h) Representative SPECT/CT images of mice after the 99mTc-αCD8/Fab and 99mTc-IgG/Fab administration and vaccination using PBS and necrotic 4T1 cells, respectively. Adopted with permission from reference [196].

Fig. 10.. Approaches for the localized modulation of the tumor microenvironment.

The current approaches mainly include the scaffold, microneedle patches, and injectable hydrogels. The scaffold helps in the activation of T cells, immune checkpoint blockade, as well as the maturation of dendritic cells. The microneedle patches and injectable hydrogel are less invasive and used for the triggered and controlled release of different immune modulators.

Fig. 11.. Application of nanomaterials in immunoimaging.

The nano-immunoimaging involves the integration of diagnostic nanomaterials for the imaging of immune cells like dendritic cells, macrophages, T cells, and NK cells.

Fig. 12

a) Size distribution of polygluocse nanoparticles (macrin) along with representative images of SEM, scale bar is 20 nm; inset: L-lysine (red) functionalized macrin (black) to attach the chelators for ⁶⁴Cu and other labels. b) Confocal images of MC38 tumor at low and high magnification in MertkGFP/+ mice. c) Reconstructed PET/CT image showing the tumors in lungs (cyan and blue) and accumulation of macrin (orange). d-e) Ex vivo PET image corresponding to in vivo highlighted tumors(d), confocal images of optically cleared lung tissue(e). f) The relation of optical (VT680) and nuclear (⁶⁴Cu) imaging. g, h) Phototoacoustic imaging with Au NR@SiO2 nanoparticles (g), NP-CIK cells (h) containing 6.7 μg of gold after peritumor injection. Part (a-f) adapted from reference [284], part (g-h) adapted from ref. adapted from reference [288].