Functional polyesters enable selective siRNA delivery to lung cancer over matched normal cells.
Conventional chemotherapeutics nonselectively kill all rapidly dividing cells, which produces numerous side effects. To address this challenge, we report the discovery of functional polyesters that are capable of delivering siRNA drugs selectively to lung cancer cells and not to normal lung cells. Selective polyplex nanoparticles (NPs) were identified by high-throughput library screening on a unique pair of matched cancer/normal cell lines obtained from a single patient. Selective NPs promoted rapid endocytosis into HCC4017 cancer cells, but were arrested at the membrane of HBEC30-KT normal cells during the initial transfection period. When injected into tumor xenografts in mice, cancer-selective NPs were retained in tumors for over 1 wk, whereas nonselective NPs were cleared within hours. This translated to improved siRNA-mediated cancer cell apoptosis and significant suppression of tumor growth. Selective NPs were also able to mediate gene silencing in xenograft and orthotopic tumors via i.v. injection or aerosol inhalation, respectively. Importantly, this work highlights that different cells respond differentially to the same drug carrier, an important factor that should be considered in the design and evaluation of all NP carriers. Because no targeting ligands are required, these functional polyester NPs provide an exciting alternative approach for selective drug delivery to tumor cells that may improve efficacy and reduce adverse side effects of cancer therapies.
Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
Yunfeng
Y
Yan
Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
Li
L
Liu
Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
Hu
H
Xiong
Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
Jason B
JB
Miller
Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
Kejin
K
Zhou
Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
Petra
P
Kos
Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
Kenneth E
KE
Huffman
Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
Sussana
S
Elkassih
Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
John W
JW
Norman
Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
Ryan
R
Carstens
Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
James
J
Kim
Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
John D
JD
Minna
Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390; daniel.siegwart@utsouthwestern.edu.
Daniel J
DJ
Siegwart
D000818:Animals; D017209:Apoptosis; D002232:Carbocyanines; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020650:Combinatorial Chemistry Techniques; D004705:Endocytosis; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy*; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D011091:Polyesters; D034741:RNA, Small Interfering; C479419:UBB protein, human; D025801:Ubiquitin
cancer; drug delivery; functional polyesters; nanoparticles; siRNA