Abstract
Mesenchymal stem cells (MSCs) accumulate specifically in both primary tumors and metastases following systemic administration. However, the poor payload capacity of MSCs limits their use in small molecule drug delivery. To improve drug payload in MSCs, we explored polymeric nanoparticles that were functionalized with transactivator of transcription (TAT) peptide. Paclitaxel loaded poly(DL-lactide-co-glycolide) (PLGA) nanoparticles (15–16% w/w paclitaxel; diameter of 225 ± 7 nm; and zeta potential of −15 ± 4 mV) were fabricated by emulsion-solvent evaporation method, followed by TAT-conjugation to the surface of nanoparticles via maleimide-thiol chemistry. Our studies demonstrated that TAT functionalization improved the intracellular accumulation and retention of nanoparticles in MSCs. Further, nano-engineering of MSCs did not alter the migration and differentiation potential of MSCs. Treatment with nano-engineered MSCs resulted in significant (p < 0.05) inhibition of tumor growth and improved survival (p < 0.0001) in a mouse orthotopic model of lung cancer compared to that with free or nanoparticle encapsulated drug. In summary, our results demonstrated that MSCs engineered using TAT functionalized nanoparticles serve as an efficient carrier for tumor specific delivery of anticancer drugs, resulting in greatly improved therapeutic efficacy.
Highlights
Tumors are characterized by uneven vascular perfusion
We evaluated nanoparticles functionalized with cell penetrating peptide (CPP) to enhance drug payload capacity of mesenchymal stem cells (MSCs)
The hydrodynamic diameter and zeta potential of nanoparticles were measured by dynamic light scattering (DLS) technique
Summary
Tumors are characterized by uneven vascular perfusion. The outer-most regions often have near normal blood flow while the inner regions can be avascular [1,2,3]. Elevated interstitial fluid pressure and rigid extracellular matrix compromise intra-tumoral solute transport [4]. This leads to poor drug delivery to the under-perfused regions within the tumor and the eventual development of drug resistance [5,6,7]. Cell-based drug delivery can overcome these critical tissue barriers faced by synthetic nano drug delivery systems [8,9,10] Because of their ability to respond to cytokine and chemokine gradients, various cell types including T cells [11], macrophages [12] and non-hematopoietic mesenchymal stem cells (MSCs) have been investigated for drug delivery [13]. Initial studies with these cell-based systems typically involved genetic modification of the cells to express anti-tumor
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