Modulation of vincristine and doxorubicin binding and release from silk films

Abstract

Sustained release drug delivery systems remain a major clinical need for small molecule therapeutics in oncology. Here, mechanisms of small molecule interactions with silk protein films were studied with cationic oncology drugs, vincristine and doxorubicin, with a focus on hydrophobicity (non-ionic surfactant) and charge (pH and ionic strength). Interactions were primarily driven by charge interactions between the positively charged drugs and the negatively charged groups within the silk films. Exploiting chemical modifications of silk further modulated the drug interactions in a controlled fashion. Increasing anionic side groups via carboxylate- and sulfonate-modifications of tyrosine side chains in the silk protein using diazonium coupling chemistry, increased drug binding and altered drug release. The effects of silk film protein crystallinity, beta sheet content, on drug binding and release was also explored. Lower crystallinity supported more rapid drug binding when compared to higher crystalline silk films. The drug release kinetics were governed by the protonation state of vincristine and doxorubicin and were tunable based on silk crystallinity and chemistry. These studies depict an approach to characterize small molecule-silk protein interactions and methods to tune drug binding and release kinetics from this protein delivery matrix.

Injectable and pH-Responsive Silk Nanofiber Hydrogels for Sustained Anticancer Drug Delivery

“…32-37 As drug carriers, silk particles, films and hydrogels show capability to stabilize the drugs and control drug release through adjusting endogenous parameters such as the crystallinity. [38][39][40][41][42] Recently, DOX-loaded silk drug-release systems with pH-responsive properties were developed and used for the treatment of cancers, suggesting feasibility of silk-based injectable hydrogels for localized chemotherapy. 2,43,44 However, similar to the injectable hydrogels reported previously, the precise control of gelation kinetics for these silk hydrogels remains a challenge.…”

Manipulation of variables in local controlled release vincristine treatment in neuroblastoma

“…Previously, Coburn et al[8], has shown that vincristine binds to silk fibroin films via electrostatic interactions, allowing for controlled release over three weeks. The foam-base system used in this work employs this same principle for vincristine binding and release.…”

“…One milliliter of the vincristine solution was added to silk fibroin foams in sterile, 1.5 mL Eppendorf tubes. The vincristine was allowed to adsorb to the silk fibroin foams as previously reported [6, 8]. …”

Sustained delivery of vincristine inside an orthotopic mouse sarcoma model decreases tumor growth

“…Under aseptic conditions, silk foams were immersed in an aqueous solution of 400 μg/mL doxorubicin hydrochloride. Doxorubicin was allowed to bind to the silk foam for one week [20, 21]. …”