Sustained Delivery of Doxorubicin via Acetalated Dextran Scaffold Prevents Glioblastoma Recurrence after Surgical Resection

Abstract

The primary cause of mortality for glioblastoma (GBM) is local tumor recurrence following standard-of-care therapies, including surgical resection. With most tumors recurring near the site of surgical resection, local delivery of chemotherapy at the time of surgery is a promising strategy. Herein drug loaded polymer scaffolds with two distinct degradation profiles were fabricated to investigate the effect of local drug delivery rate on GBM recurrence following surgical resection. The novel biopolymer, acetalated dextran (Ace-DEX), was compared to commercially available polyester, poly(L-lactide) (PLA). Steady state doxorubicin (DXR) release from Ace-DEX scaffolds was found to be faster when compared to scaffolds comprised of PLA, in vitro. This increased drug release rate translated to improved therapeutic outcomes in a novel surgical model of orthotopic glioblastoma resection and recurrence. Mice treated with DXR loaded Ace-DEX scaffolds (Ace-DEX/10DXR) resulted in 57% long term survival out to study completion at 120 days compared to 20% survival following treatment with DXR loaded PLA scaffolds (PLA/10DXR). Additionally, all mice treated with PLA/10DXR scaffolds exhibited disease progression by day 38, as defined by a five-fold growth in tumor bioluminescent signal. In contrast, 57% of mice treated with Ace-DEX/10DXR scaffolds displayed a reduction in tumor burden, with 43% exhibiting complete remission. These results underscore the importance of polymer choice and drug release rate when evaluating local drug delivery strategies to improve prognosis for GBM patients undergoing tumor resection.

Functional Electrospun Fibers for Local Therapy of Cancer

“…Similarly, anti-cancer drug-loaded electrospun fibrous scaffolds fabricated from the biopolymer acetalated dextran (Ace-DEX) were discovered to have tailored drug release profile due to its tunable degradation rates [45]. Taking advantage of these unique properties, Ace-DEX nanofibers were fabricated to treat GBM recurrence following surgical resection, and proven to have a higher long-term survival rate (57%) compared to PLA nanofibers (20%) [46]. In another study, a drug-loaded sheet-and disc-shaped sub-micro fiber implant for postsurgical glioma therapy was developed, taking advantage of their different drug release properties and the implantability of the fibrous scaffold in the tumor resection area [47].…”

Acetalated dextran based nano- and microparticles: synthesis, fabrication, and therapeutic applications

“…For example, Ace-DEX, synthesized from 2-ethoxypropene, have been thoroughly investigated. [12][13][14][15][16][17] Compared with Ac-DEX, Ace-DEX has similar physiochemical properties and pH-dependent degradation by hydrolysis. 12 The most significant difference is the degradation products (acetone and ethanol), instead of acetone and methanol as in the case of Ac-DEX.…”

Addressing BBB Heterogeneity: A New Paradigm for Drug Delivery to Brain Tumors

“…These PLGA wafers used a pre-encapsulation process and reported 25% long-term survivors (survived >120 days compared to median survival of 28 days) in the F344 rat model [ 141 ]. Other chemotherapeutic agents that have been explored for sustained local delivery via polymeric implants include taxol, camptothecin, minocycline, doxorubicin, and others [ 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 ]. Novel polymeric implants and microchips can be used to deliver several drugs locally at varying time points in a controlled manner, and various formulations such as nanoparticles, liposomes, and microparticles can also be delivered via these implants.…”