Nanoparticle delivery systems in cancer vaccines

Abstract

Therapeutic strategies that involve the manipulation of the host's immune system are gaining momentum in cancer research. Antigen-loaded nanocarriers are capable of being actively taken up by antigen-presenting cells (APCs) and have shown promising potential in cancer immunotherapy by initiating a strong immunostimulatory cascade that results in potent antigen-specific immune responses against the cancer. Such carrier systems offer versatility in that they can simultaneously co-deliver adjuvants with the antigens to enhance APC activation and maturation. Furthermore, modifying the surface properties of these nanocarriers affords active targeting properties to APCs and/or enhanced accumulation in solid tumors. Here, we review some recent advances in these colloidal and particulate nanoscale systems designed for cancer immunotherapy and the potential for these systems to translate into clinical cancer vaccines.

Figure 1

Scanning electron micrograph of cationized gelatin nanoparticles. Reprinted with permission from (139) © Springer Inc. (2008).

Figure 2

CpG-loaded nanoparticles elicit an OVA-specific antitumor response. In brief, B16-OVA or B16 tumors were implanted s.c. in C57BL/6 mice after four immunizations with 50 μg OVA and 100 μg free CpG or NP-bound CpG (n = 5). A, Immunization with OVA and NP-CpG significantly reduced growth of B16-OVA tumors compared to untreated mice (p < 0.03 at all time points from day 6) or to mice treated with OVA alone 0.02 from day 13). No effect of immunization was seen in the wild-type B16 tumors (n.s. at all time points). B, In mice with B16-OVA tumors, immunization with OVA and NP-CpG increased survival times compared with untreated mice (p = 0.009) or to mice treated with OVA alone (p = 0.003). No effect of immunization on survival was seen in the wild-type B16 tumors. Similar results were obtained in two independent experiments. Reprinted with permission from (139) © Springer Inc. (2008).

Figure 3

The immunotherapy effect of challenged B16-MAGE-1 melanoma with the tumor vaccine. Mice were sc. inoculated with B16-MAGE-1 tumor cells (1 x 10⁵ cells/mouse, respectively). Seven days later, they were randomly divided into six groups (n = 6 mice/group) and vaccinated as described in the Fig. 2. Data presented are mean ± SEM. Vaccination with NE (MHS), whether via sc. route or po. route, signicantly delayed tumor growth compared with vaccination using MHS or NE (−), and there were no statistical differences between NE (MHS)-sc. and NE (MHS)-po. group at the observation points. Reprinted with permission from (145) © Springer Inc. (2008).

Figure 4

Induction of Ag-specific cellular and humoral immune responses by OVA-NPs. Mice were immunized with either PBS, OVA, OVA-NPs, or CFA plus OVA through their footpads. A, Spleen cells were restimulated with the OVA257–264 peptide and IL-2. The spleen cells were examined for their cytolytic activity to peptide-treated or untreated EL4 target cells at various E:T ratios by a standard 51Cr-releasing assay. The experiments were performed in triplicate, and data are expressed as mean ± SD. The results are a representative of three separate experiments. The difference in specific lysis between the OVA-NPs group and the CFA plus OVA group is statistically significant (p < 0.05) at an E:T ratio of 50. B, Spleen cells were restimulated with the OVA257–264 peptide or OVA protein. IFN-γ producing T cells were counted and expressed as the spot forming unit (SFU) per one million cells. Data represent mean ± SD for three to four separate experiments. *,p < 0.05. C and D, Sera were tested for their Ab titers of OVA-specific IgG and its subclasses as determined by ELISA. Data represent mean ± SD of endpoint titers for three to four separate experiments. *, p < 0.05, **, p < 0.005. Reprinted with permission from (154) © The American Association of Immunologists Inc. (2007).

Figure 5

Anti-tumor effect elicited by immunization with γ-PGA NP/OVA. C57BL/6 mice were immunized subcutaneously with γ-PGA NP/OVA (●; 100 μg OVA, ○; 10 μg OVA), CFA/OVA (□ 100 μg OVA), OVA solution (◆; 100 μg OVA), or PBS (△). Ten days later, 10⁶ E.G7-OVA cells were inoculated intradermally into the flank of each mouse; then the tumor volume was monitored. Each point represents the mean ± S.E. from 5 to 9 mice. Statistical significance of γ-PGA NP/OVA (100 μg OVA) vs. CFA/OVA on day 18 was determined by Student’s t-test (^*P < 0.05). Reprinted with permission from (156) © Elsevier Inc. (2008).