Conjugation of pH-responsive nanoparticles to neural stem cells improves intratumoral therapy

Abstract

Intratumoral drug delivery is an inherently appealing approach for concentrating toxic chemotherapies at the site of action. This mode of administration is currently used in a number of clinical treatments such as neoadjuvant, adjuvant, and even standalone therapies when radiation and surgery are not possible. However, even when injected locally, it is difficult to achieve efficient distribution of chemotherapeutics throughout the tumor. This is primarily attributed to the high interstitial pressure which results in gradients that drive fluid away from the tumor center. The stiff extracellular matrix also limits drug penetration throughout the tumor. We have previously shown that neural stem cells can penetrate tumor interstitium, actively migrating even to hypoxic tumor cores. When used to deliver therapeutics, these migratory neural stem cells result in dramatically enhanced tumor coverage relative to conventional delivery approaches. We recently showed that neural stem cells maintain their tumor tropic properties when surface-conjugated to nanoparticles. Here we demonstrate that this hybrid delivery system can be used to improve the efficacy of docetaxel-loaded nanoparticles when administered intratumorally. This was achieved by conjugating drug-loaded nanoparticles to the surface of neural stem cells using a bond that allows the stem cells to efficiently distribute nanoparticles throughout the tumor before releasing the drug for uptake by tumor cells. The modular nature of this system suggests that it could be used to improve the efficacy of many chemotherapy drugs after intratumoral administration.

Intraperitoneal Administration of Neural Stem Cell–Nanoparticle Conjugates Targets Chemotherapy to Ovarian Tumors

“…11 Drug-loaded polymeric micelles that were surface conjugated to NSCs showed increased efficacy relative to free NPs following an IT injection in a xenograft model of breast cancer. 12 Furthermore, relative to free nanorods, IT injection of gold nanorods loaded inside of the NSCs had improved distribution throughout the tumor, resulting in significantly increased tumor killing following laser application in a xenograft model of breast cancer. 13, 14 This work is part of an emerging body of literature demonstrating that many types of tumor tropic cells can be used to improve NP delivery and retention within tumors, including mesenchymal stem cells, 15 macrophages, 16 and T-cells.…”

Concise Review: Neural Stem Cell-Mediated Targeted Cancer Therapies

“…Furthermore, the NPs can be up to ∼fivefold larger than those typically used for cancer therapies, which translates into a >100‐fold increase in the loading potential of a typical small molecular weight chemotherapeutics. The utility of this approach has also been investigated in preclinical orthotopic breast and ovarian cancer settings .…”

“…STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals, Inc. on behalf of AlphaMed Press a typical small molecular weight chemotherapeutics. The utility of this approach has also been investigated in preclinical orthotopic breast [43] and ovarian cancer settings [16].…”

Exploiting homing abilities of cell carriers: Targeted delivery of nanoparticles for cancer therapy

“…Another study by Mooney et al demonstrated that pH-responsive (poly(ethylene glycol)- poly((diisopropylamino)ethyl methacrylate) (PEG-PDPAEMA) nanoparticles containing docetaxel could be functionalized onto the surface of NSCs using biotin/avidin conjugation chemistry. Intratumoral injection of NSCs loaded with the docetaxel pH-responsive nanoparticles demonstrated activity for the drug but no efficacy study was performed [57]. Recently, Cao et al demonstrated tumor tropism through intraperitoneal injection of NSCs with either surface conjugated or internalized silica nanoparticles into a metastatic ovarian cancer model.…”