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. 2010 Oct 19;107(42):17939-44.
doi: 10.1073/pnas.1011368107. Epub 2010 Oct 4.

Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy

Nagesh Kolishetti  1 , Shanta Dhar, Pedro M Valencia, Lucy Q Lin, Rohit Karnik, Stephen J Lippard, Robert Langer, Omid C Farokhzad
Affiliations

Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy

Nagesh Kolishetti et al. Proc Natl Acad Sci U S A. .

Abstract

The genomic revolution has identified therapeutic targets for a plethora of diseases, creating a need to develop robust technologies for combination drug therapy. In the present work, we describe a self-assembled polymeric nanoparticle (NP) platform to target and control precisely the codelivery of drugs with varying physicochemical properties to cancer cells. As proof of concept, we codelivered cisplatin and docetaxel (Dtxl) to prostate cancer cells with synergistic cytotoxicity. A polylactide (PLA) derivative with pendant hydroxyl groups was prepared and conjugated to a platinum(IV) [Pt(IV)] prodrug, c,t,c-[Pt(NH(3))(2)(O(2)CCH(2)CH(2)COOH)(OH)Cl(2)] [PLA-Pt(IV)]. A blend of PLA-Pt(IV) functionalized polymer and carboxyl-terminated poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol) copolymer in the presence or absence of Dtxl, was converted, in microfluidic channels, to NPs with a diameter of ∼100 nm. This process resulted in excellent encapsulation efficiency (EE) and high loading of both hydrophilic platinum prodrug and hydrophobic Dtxl with reproducible EEs and loadings. The surface of the NPs was derivatized with the A10 aptamer, which binds to the prostate-specific membrane antigen (PSMA) on prostate cancer cells. These NPs undergo controlled release of both drugs over a period of 48-72 h. Targeted NPs were internalized by the PSMA-expressing LNCaP cells via endocytosis, and formation of cisplatin 1,2-d(GpG) intrastrand cross-links on nuclear DNA was verified. In vitro toxicities demonstrated superiority of the targeted dual-drug combination NPs over NPs with single drug or nontargeted NPs. This work reveals the potential of a single, programmable nanoparticle to blend and deliver a combination of drugs for cancer treatment.

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Conflict of interest statement

Conflict of interest statement: O.C.F. discloses his financial interest in BIND Biosciences and Selecta Biosciences, two biotechnology companies developing nanoparticle technologies for medical applications. BIND and Selecta did not support the aforementioned research, and currently these companies have no rights to any technology or intellectual property developed as part of this research. BIND and Selecta are biopharmaceutical companies founded by O.C.F. and R.L., where they both serve as members of the Board of Directors and Scientific Advisory Board.

Figures

Scheme 1.
Scheme 1.
Synthesis of PLA-Pt(IV) by coupling succinic acid-modified Pt(IV) prodrug with PLA-OH.
Fig. 1.
Fig. 1.
Design and construction of NPs.
Fig. 2.
Fig. 2.
Synthesis (A) and characterization of NPs via DLS (B) and TEM (C).
Fig. 3.
Fig. 3.
In vitro release kinetics of encapsulated platinum (circle) and docetaxel (square) in PBS at 37 °C from NPs.
Fig. 4.
Fig. 4.
In vitro toxicity of PLA-OH-NP.
Fig. 5.
Fig. 5.
Endocytosis of PSMA targeted NPs in LNCaP cells. Green fluorescent 22-NBD-cholesterol was coencapsulated in the PLGA-b-PEG nanoparticles and PSMA aptamers were conjugated to the surface of the particles. The early endosomes were visualized in red by using the early endosome marker EEA-1.
Fig. 6.
Fig. 6.
Visualization of Pt-1,2,-d(GpG) intrastrand cross-links in the nuclear DNA of LNCaP cells after treatment with PLA-Pt-NP-Apt and PLA-Pt-(Dxtl)-NP-Apt. Nuclei were stained with Hoeshst (blue) and Pt-1,2-d(GpG) in DNA were visualized using Mab R-C18 (green).
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