Despite the great progress in nanomedicine, nanoparticle-based drug delivery is still suffering from the low accumulation of therapeutic agents at tumor sites. To solve that problem, Prof. Shen’s group has designed and prepared a multistage carrier platform. The platform consists of micro-sized discoidal silicon particles that are loaded with a pH-responsive polymeric prodrug poly(L-glutamic acid)-Doxorubicin (pDox). Once injected, the silicon particles can accumulate at tumor sites due to natural tropism and favorable vascular dynamics. Meanwhile, the pDox in the silicon particles can self-assemble into nanoparticles, which will subsequently be released to the tumor tissue. In that way, the pDox-loaded silicon particle functions as an injectable nanoparticle generator (iNPG). Furthermore, after being internalized into tumor cells, the pDox nanoparticles can be transported to the perinuclear regions, where the Dox molecules are cut from the poly(L-glutamic acid) upon the decrease in pH. Compared to its individual components or current therapeutic formulations, the iNPG-pDox shows enhanced efficacy in MDA-MB-231 and 4T1 mouse models of metastatic breast cancer. cGMP production of the iNPG-pDox is now ongoing.
2. Inflammatory tumor vasculature-targeting delivery system for small molecule inhibitors and therapeutic siRNA
Bone metastasis frequently occurs with multiple types of solid tumors. Treatment of bone metastasis remains challenging because drug molecules cannot be efficiently delivered to the tumor site by directly targeting the metastatic tumor cells. To address that issue, Prof. Shen’s lab has developed a thioaptamer (ESTA) that can selectively bind to the E-selectin overexpressed on the vasculature of tumor and inflammatory tissues. Using the ESTA as a ligand, Shen’s team has successfully prepared the tumor vasculature-targeting multistage vector (MSV), which can preferentially accumulate in the bone metastatic tumor tissue. Different therapeutic agents can be loaded into the MSV. For example, siRNA-encapsulating MSVs have been prepared by loading ESTA-modified porous silicon particles with polyplex micelles formed by siRNA and PEG-PEI. After the ESTA-MSV is delivered to the tumor tissue, the silicon particle will be slowly degraded and the released polyplex micelle will function as a secondary carrier. It has been found that the accumulation of the ESTA-MSV in the bone metastatic tumor is positively correlated with the level of E-selectin expression. Targeted delivery of STAT3 siRNA by the ESTA-MSV can inhibit the expression of STAT3 by about 50% in the bone metastatic cells. Weekly systemic administration of the ESTA-MSV/STAT3 siRNA significantly extends the survival of mice bearing MDA-MB-231 bone metastasis.
3. Antitumor nanovaccine platform for efficient cancer immunutherapy
Cancer vaccine has proved to be a promising therapeutic agent for the treatment of tumors. Combining immunotherapy and nanotechnology, Prof. Shen’s lab has prepared different nanovaccine platforms by loading antigens into nano- and micro-particles. For example, protein/peptide antigens (encapsulated in liposomes) have been loaded into porous silicon micro-particles (PSMs) to achieve stronger immune responses. The antigens in the PSMs exhibits prolonged early endosome localization and enhanced cross-presentation through both proteasome- and lysosome-dependent pathways. Meanwhile, phagocytosis of the PSM by the dendritic cells (DCs) can induce IFN-I response through a TRIF- and MAVS-dependent pathway. The DCs primed with the PSMs containing the HER2 antigen produces robust CD8 T cell-dependent anti-tumor immunity in mice bearing HER2+ mammary gland tumors. In particular, the vaccination by PSM-HER2 leads to a more immune-competent tumor microenvironment with elevated expression of intra-tumor IFN-I and MHCII, abundant CD11c+ DC infiltration, and tumor-specific cytotoxic T cell responses. Therefore, the PSM shows great potential as an immune adjuvant to potentiate DC-based cancer immunotherapy.
In addition to protein and peptide antigens, antigen-encoding mRNA has also been employed for the preparation of nanovaccines. Herein, the mRNA is complexed with the poly(beta-amino ester) (PBAE) to form the polyplex core, which is further encapsulated in a EDOPC/DOPE/DSPE-PEG liposome. The resultant structure, which is called lipopolyplex, can effectively protect the mRNA from the RNase attack. Once the lipopolyplex is internalized by DCs, the mRNA will be released to the cytosol for antigen production. What’s more, the lipopolyplex also displays intrinsic adjuvant activity by potently promoting the expression of interferon-β and interleukin-12 in the DCs. It has been demonstrated that the DCs treated with the mRNA vaccine show enhanced antigen presentation capability. The lung metastasis model of B16-OVA melanoma treated with OVA mRNA-containing lipopolyplex shows over 90% fewer tumor nodules compared to the control group.