Localized chemotherapy approaches and advanced drug delivery strategies: a step forward in the treatment of peritoneal carcinomatosis from ovarian cancer.

Peritoneal carcinomatosis (PC) is a common outcome of epithelial ovarian carcinoma and is the leading cause of death for these patients. Tumor location, extent, peculiarities of the microenvironment, and the development of drug resistance are the main challenges that need to be addressed to improve therapeutic outcome. The development of new procedures such as HIPEC (Hyperthermic Intraperitoneal Chemotherapy) and PIPAC (Pressurized Intraperitoneal Aerosol Chemotherapy) have enabled locoregional delivery of chemotherapeutics, while the increasingly efficient design and development of advanced drug delivery micro and nanosystems are helping to promote tumor targeting and penetration and to reduce the side effects associated with systemic chemotherapy administration. The possibility of combining drug-loaded carriers with delivery via HIPEC and PIPAC represents a powerful tool to improve treatment efficacy, and this possibility has recently begun to be explored. This review will discuss the latest advances in the treatment of PC derived from ovarian cancer, with a focus on the potential of PIPAC and nanoparticles in terms of their application to develop new therapeutic strategies and future prospects.

Combination of hyaluronic acid conjugates with immunogenic cell death inducer and CpG for glioblastoma local chemo-immunotherapy elicits an immune response and induces long-term survival.

The efficacy of standard glioblastoma (GBM) treatments has been limited due to the highly immunosuppressive tumor immune microenvironment, interpatient tumor heterogenicity and anatomical barriers, such as the blood brain barrier. In the present work, we hypothesized that a new local therapy based on the combination of doxorubicin (DOX) as an immunogenic cell death (ICD) inducer and CpG, a Toll-like receptor (TLR)-9 agonist, would act synergistically to eradicate GBM. DOX and CpG were first tested in an orthotopic GL261 GBM model showing enhanced survival. To improve the outcome with a reduced dose, we designed bioresponsive hyaluronic acid (HA)-drug conjugates for effective in situ chemoimmunotherapy. HA was derivatized with CpG. The new HA-CpG conjugate showed high efficacy in re-educating protumoral M2-like microglia into an antitumoral M1-like phenotype, inducing the expression of immune-stimulatory cytokines. DOX was also conjugated to HA. DOX conjugation increased ICD induction in GL261 cells. Finally, a combination of the conjugates was explored in an orthotopic GL261 GBM model. The local delivery of combined HA-DOX + HA-CpG into the tumor mass elicited antitumor CD8+ T cell responses in the brain tumor microenvironment and reduced the infiltration of M2-like tumor-associated macrophages and myeloid-derived suppressor cells. Importantly, the combination of HA-DOX and HA-CpG induced long-term survival in >66% of GBM-bearing animals than other treatments (no long-term survivor observed), demonstrating the benefits of conjugating synergistic drugs to HA nanocarrier. These results emphasize that HA-drug conjugates constitute an effective drug delivery platform for local chemoimmunotherapy against GBM and open new perspectives for the treatment of other brain cancers and brain metastasis.

Design of Bio-Responsive Hyaluronic Acid-Doxorubicin Conjugates for the Local Treatment of Glioblastoma.

Glioblastoma is an unmet clinical need. Local treatment strategies offer advantages, such as the possibility to bypass the blood-brain barrier, achieving high drug concentrations at the glioblastoma site, and consequently reducing systemic toxicity. In this study, we evaluated the feasibility of using hyaluronic acid (HA) for the local treatment of glioblastoma. HA was conjugated to doxorubicin (DOX) with distinct bio-responsive linkers (direct amide conjugation HA-NH-DOX), direct hydrazone conjugation (HA-Hz-DOX), and adipic hydrazone (HA-AdpHz-DOX). All HA-DOX conjugates displayed a small size (less than 30 nm), suitable for brain diffusion. HA-Hz-DOX showed the best performance in killing GBM cells in both 2D and 3D in vitro models and displayed superior activity in a subcutaneous GL261 tumor model in vivo compared to free DOX and other HA-DOX conjugates. Altogether, these results demonstrate the feasibility of HA as a polymeric platform for the local treatment of glioblastoma and the importance of rationally designing conjugates.