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Silk fibroin-derived nanoparticles for biomedical applications The treatment of disease in the future will be influenced by the ability to produce therapeutic formulations that have high availability at the disease site, sustained and long-term release, with minimal to no toxicity to healthy tissues. Biologically derived delivery systems offer promise in this regard owing to minimization of adverse effects while increasing the efficacy of the entrapped therapeutic. Silk fibroin nanoparticles overcome barriers set by synthetic nondegradable nanoparticles made of silicone, polyethylene glycol and degradable polylactic acid–polyglycolic acid polymers. Silk fibroin-mediated delivery has demonstrated high efficacy in breast cancer cells. While the targeting is associated with the specificity of entrapped therapeutic for the diseased cells, silk fibroin-derived particles enhance intracellular uptake and retention resulting in downmodulation of more than one pathway due to longer availability of the therapeutic. The mechanism of targeting for the nanoparticle is based on the silk fibroin composition, b-sheet structure and self-assembly into b-barrels. KEYWORDS: antiparallel b‑pleated sheets n biodegradable n cancer cells n nanoparticles n quantum dots n silk fibroin
Anshu B Mathur†1 & Vishal Gupta1 Tissue Regeneration & Molecular Cell Engineering Labs (TRAMCEL) , Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 602, Houston, TX 77030, USA † Author for correspondence: Tel.: +1 713 563 7568 Fax: +1 713 563 0231
[email protected] 1
Barriers to therapeutic delivery into the diseased site are numerous and require careful consideration when designing a new therapeutic [1] . The efficacy of the therapeutic is dependent upon its mode of delivery and its potency at the site of disease. Intravenous delivery to a diseased site can vary in efficacy depending on the properties of the diseased site and the delivery vehicle. For example, at the site of a solid tumor, key issues that make therapeutic delivery challenging at the micro- and macro-scales are heterogeneous vascular architecture, heterogeneous vascular permeability, high interstitial pressures in the necrotic core, large interstitial distance between the tissue mass and vessels, low convective transport, acidic pH, hypoxia and a lack of lymphatic drainage [2–4] . In addition, owing to lack of specificity of the delivery device for tumor cells, administration of a high dosage of the drug causes drug resistance and toxicity to normal tissues. In the last two decades, many studies have focused on the development of drug-delivery systems to achieve controlled release and mechanisms to enable drug targeting to specific tissue (tumor) sites by utilization of microparticles and nanoparticles [5–11] . Targeting of a diseased site or cells via a nanoparticle requires several considerations:
Targeting efficiency of the encapsulated thera peutic itself towards the tumor once the nanoparticle gets into the cell; Clearance of the unused nanoparticles from the body whether it is via biodegradation or native particles via liver or kidneys or lungs; Accumulation of the particles in normal tissues and its effects, if any.
Ability of the particle to deliver the encapsulated therapeutic to the diseased site by overcoming nanoscale intra- and inter-molecular forces;
An efficient nanoscale delivery system would be expected to improve efficacy versus the naked therapeutic and should either maintain or enhance the effect of the encapsulated therapeutic. A biologically derived and biodegradable nanoscale delivery agent with no toxic byproducts would allow the delivery of the therapeutic without compromising efficacy. If the biologically derived carrier has chemical and/or structural characteristics that enhance uptake by the cells, then the carrier would improve efficacy tremendously. A silk fibroin (SF)-based delivery vehicle [9,12,13] is an example of such a biologically derived delivery system that overcomes barriers set by synthetic nondegradable nanoparticles made of silicone [14,15] or polyethylene glycol [16] and synthetic degradable particles made of polylactic acid and its analogs (Boxes 1 & 2) [17] . Silk fibroin is a fibrous protein polymer obtained from the cocoons of domesticated silkworms, such as Bombyx mori, and dragline threads of orb-weaving spiders, such as Nephila
10.2217/NNM.10.51 © Anshu B. Mathur
Nanomedicine (2010) 5(5), 807–820
ISSN 1743-5889
807
Review
Mathur & Gupta
Box 1. Advantages of silk fibroin-derived therapeutic nanoparticles†.
Biologically derived composition that is biocompatible Biodegradable in vivo 50 µm) [34] , submicron SF particles (
