Abstract
The success of anti-cancer therapies largely depends on the ability of the therapeutics to reach their designated cellular and intracellular target sites, while minimizing accumulation and action at non-specific sites. Surface modification of nanoparticulate carriers with poly(ethylene glycol) (PEG)/poly(ethylene oxide) (PEO) has emerged as a strategy to enhance solubility of hydrophobic drugs, prolong circulation time, minimize non-specific uptake, and allow for specific tumor-targeting through the enhanced permeability and retention effect. Furthermore, PEG/PEO modification has emerged as a platform for incorporation of active targeting ligands, thereby providing the drug and gene carriers with specific tumor-targeting properties through a flexible tether. This review focuses on the recent developments surrounding such PEG/PEO-surface modification of polymeric nanocarriers to promote tumor-targeting capabilities, thereby enhancing efficacy of anti-cancer therapeutic strategies.
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American Cancer Society. Cancer Facts & Figures 2006. http://www.cancer.org/docroot/MED/content/MED_1_1_Most-Requested_Graphs_and_Figures_2006.asp (accessed September 12, 2006), part of www.cancer.org (accessed September 12, 2006).
U.S. National Institute of Health. Cancer Statistics http://www.cancer.gov/statistics/ (accessed September 15, 2006).
S. H. Jang, M. G. Wientjes, D. Lu, and J. L.-S. Au. Drug delivery and transport to solid tumors. Pharm. Res. 20:1337–1350 (2003).
Y. Matsumura and H. Maeda. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent SMANCS. Cancer Res. 46:6387–6392 (1986).
H. Maeda, J Wu, T. Sawa, Y. Matsumura, and K. Hori. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J. Control. Rel. 65:271–284 (2000).
D. E. Owens, III, and N. A. Peppas. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int. J. Pharm. 307:93–102 (2006).
V. P. Torchilin. Recent approaches to intracellular delivery of drugs and DNA and organelle targeting. Annu. Rev. Biomed. Eng. 8:343–375 (2006).
USFDA Center for Drug Evaluation and Research. Guidance for Indrustry, Scale-up and Post approval Changes: Chemistry, Manufacturing and Control. http://www.fda.gov/cder/guidance/cmc5.pdf (Accessed August 24, 2006), part of http://www.fda.gov/cder (accessed August 24, 2006).
R. Duncan. The dawning era of polymer therapeutics. Nat. Rev. Drug Discov. 2:347–360 (2003).
K. E. Uhrich S. M. Cannizzaro, R. S. Langer, and K. M. Shakesheff. Polymeric systems for controlled drug release. Chem. Rev. 99:3181–3198 (1999).
F. M. Veronese and G. Pasut. PEGylation, successful approach to drug delivery. Drug Discov. Today 10:1451–1458 (2005).
J. M. Harris. Poly(ethylene glycol) Chemistry: Biotechnical and Biomedical Applications. Plenum Press, New York, 1992.
M. L. Adams, A. Lavasanifar, and G. S. Kwon. Amphiphilic block copolymers for drug delivery. J. Pharm. Sci. 92:1343–1355 (2003).
N. Kumar, M. N. Ravikumar, and A. J. Domb. Biodegradable block copolymers. Adv. Drug Deliv. Rev. 53:23–44 (2001).
M. Yokoyama. Block copolymers as drug carriers. Crit. Rev. Ther. Drug Carr. Syst. 9:213–248 (1992).
D. B. Shenoy and M. M. Amiji. Poly(ethylene oxide)-modified poly(epsilon-caprolactone) nanoparticles for targeted delivery of tamoxifen in breast cancer. Int. J. Pharm. 293:261–270 (2005).
USFDA. Interactive Ingredient Guide (Redacted) January 1996. http://www.fda.gov/cder/drug/iig/default.htm (accessed August 26, 2006), part of http://www.fda.gov/cder (accessed August 26, 2006).
T. Yamaoka, Y. Tabata, and Y. Ikada. Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J. Pharm. Sci. 83:601–606 (1994).
C. Monfardini, O. Schiavon, P. Caliceti, M. Morpurgo, J. M. Harris, and F. M. Veronese. A branched monomethoxypoly(ethylene glycol) for protein modification. Bioconjug. Chem. 6:62–69 (1995).
S. Kommareddy, S. B. Tiwari, and M. M. Amiji. Long-circulating polymeric nanovectors for tumor-selective gene delivery. Technol. Cancer Res. Treat. 4:615–625 (2005).
M. Hamidi, A. Azadi, and P. Rafiei. Pharmacokinetic consequences of pegylation. Drug Deliv. 13:399–409 (2006).
R. Gref, Y. Minamitake, M. T. Peracchia, V. Trubetskoy, V. Torchilin, and R. Langer. Biodegradable long-circulating polymeric nanospheres. Science 263:1600–1603 (1994).
R. Gref, A. Domb, P. Quellec, T. Blunk, R. H. Müller, J. M. Verbavatz, et al. The controlled intravenous delivery of drugs using PEG-coated sterically stabilized nanospheres. Adv. Drug Deliv. Rev. 16:215–233 (1999).
S. M. Moghimi, H. Hedeman, I. S. Muir, L. Illum, and S. Davis. An investigation of the filtration capacity and the fate of large filtered sterically-stabilized microspheres in rat spleen. Biochem. Biophys. Acta 1157:233–240 (1993).
S. M. Moghimi, A. C. Hunter, and J. C. Murray. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol. Rev. 53:283–318 (2001).
S. Mao, M. Neu, O. Germershaus, O. Merkel, J. Sitterberg, U. Bakowsky, et al. Influence of polyethylene glycol chain length on the physicochemical and biological properties of poly(ethylene imine)-graft-poly(ethylene glycol) block copolymer/SiRNA polyplexes. Bioconjug. Chem. 17:1209–1218 (2006).
S. Kommareddy and M. Amiji. Biodistribution and pharmacokinetic analysis of long-circulating thiolated gelatin nanoparticles following systemic administration in breast cancer-bearing mice. J. Pharm. Sci. 96:397–407 (2007).
D. Shenoy, S. Little, R. Langer, and M. Amiji. Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs: part 2. In vivo distribution and tumor localization studies. Pharm. Res. 22:2107–2114 (2005).
G. Kaul and M. Amiji. Biodistribution and targeting potential of poly(ethylene glycol)-modified gelatin nanoparticles in subcutaneous murine tumor model. J. Drug Target 12:585–591 (2004).
G. Kaul and M. Amiji. Long-circulating poly(ethylene glycol)-modified gelatin nanoparticles for intracellular delivery. Pharm. Res. 19:1061–1077 (2002).
D. Shenoy, S. Little, R. Langer, and M. Amiji. Poly(ethylene oxide)-modified poly (beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs: part 1. In vitro evaluations. Mol. Pharmacol. 2:357–366 (2005).
S. Kommareddy and M. Amiji. Preparation and evaluation of thiol-modified gelatin nanoparticles for intracellular DNA delivery in response to glutathione. Bioconjug. Chem. 16:1423–1432 (2005).
L. K. Shah and M. M. Amiji. Intracellular delivery of saquinavir in biodegradable polymeric nanoparticles for HIV/AIDS. Pharm. Res. 23:2638–2645 (2006).
J. S. Chawla and M. M. Amiji. Biodegradable poly (epsilon-caprolactone) nanoparticles for tumor-targeted delivery of tamoxifen. Int. J. Pharm. 249:127–138 (2002).
I. Brigger, J. Morizet, L. Laudani, G. Aubert, M. Appel, V. Velasco, et al. Negative preclinical results with stealth nanospheres-encapsulated Doxorubicin in an orthotopic murine brain tumor model. J. Control. Release 100:29–40 (2004).
Z. Xu, W. Gu, J. Huang, H. Sui, Z. Zhou, Y. Yang, et al. In vitro and in vivo evaluation of actively targetable nanoparticles for paclitaxel delivery. Int. J. Pharm. 288:361–368 (2005).
C. Fang, B. Shi, Y. Y. Pei, M. H. Hong, J. Wu, and H. Z. Chen. In vivo tumor targeting of tumor necrosis factor-alpha-loaded stealth nanoparticles: effect of MePEG molecular weight and particle size. Eur. J. Pharm. Sci. 27:27–36 (2006).
G. Kaul and M. Amiji. Cellular interactions and in vitro DNA transfection studies with poly(ethylene glycol)-modified gelatin nanoparticles. J. Pharm. Sci. 94:184–198 (2005).
G. Kaul and M. Amiji. Tumor-targeted gene delivery using poly(ethylene glycol)-modified gelatin nanoparticles: in vitro and in vivo studies. Pharm. Res. 22:951–961 (2005).
C. Sun, R. Sze, and M. Zhang. Folic acid-PEG conjugated superparamagnetic nanoparticles for targeted cellular uptake and detection by MRI. J. Biomed. Mater. Res. 78:550–557 (2006).
S. H. Kim, J. H. Jeong, K. W. Chun, and T. G. Park. Target-specific cellular uptake of PLGA nanoparticles coated with poly(L-lysine)-poly(ethylene glycol)-folate conjugate. Langmuir 21:8852–8857 (2005).
M. O. Oyewumi, S. Liu, J. A. Moscow, and R. J. Mumper. Specific association of thiamine-coated gadolinium nanoparticles with human breast cancer cells expressing thiamine transporters. Bioconjug. Chem. 14:404–411 (2003).
R. M. Schiffelers, A. Ansari, J. Xu, Q. Zhou, Q. Tang, G. Storm, et al. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res. 32:e149 (2004).
D. Simberg, T. Duza, J. H. Park, M. Essler, J. Pilch, L. Zhang, et al. Biomimetic amplification of nanoparticle homing to tumors. PNAS 104:932–936 (2007).
U. B. Nielsen, D. B. Kirpotin, E. M. Pickering, K. Hong, J. W. Park, M. Refaat Shalaby, et al. Therapeutic efficacy of anti-ErbB2 immunoliposomes targeted by a phage antibody selected for cellular endocytosis. Biochem. Biophys. Acta 1591:109–118 (2002).
N. C. Bellocq, S. H. Pun, G. S. Jensen, and M. E. Davis. Transferrin-containing, cyclodextrin polymer-based particles for tumor-targeted gene delivery. Bioconjug. Chem. 14:1122–1132 (2003).
X. Gao, W. Tao, W. Lu, Q. Zhang, Y. Zhang, X. Jiang, et al. Lectin-conjugated PEG-PLA nanoparticles: preparation and brain delivery after intranasal administration. Biomaterials 27:3482–3490 (2006).
T. A. Elbayoumi and V. P. Torchilin. Enhanced accumulation of long-circulating liposomes modified with the nucleosome-specific monoclonal antibody 2C5 in various tumours in mice: gamma-imaging studies. Eur. J. Nucl. Med. Mol. Imaging 33:1196–1205 (2006).
M. E. Hayes, D. C. Drummond, K. Hong, W. W. Zheng, V. A. Khorosheva, J. A. Cohen, et al. Increased target specificity of anti-HER2 genospheres by modification of surface charge and degree of PEGylation. Mol. Pharmacol. 3:726–736 (2006).
Y. I. Jeong, S. J. Seo, I. K. Park, H. C. Lee, I. C. Kang, T. Akaike, et al. Cellular recognition of paclitaxel-loaded polymeric nanoparticles composed of poly(gamma-benzyl L-glutamate) and poly(ethylene glycol) diblock copolymer endcapped with galactose moiety. Int. J. Pharm. 296:151–161 (2005).
O. C. Farokhzad, J. Cheng, B. A. Teply, I. Sherifi, S. Jon, P. W. Kantoff, et al. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. PNAS 103:6315–6320 (2006).
G. Russell-Jones, K. McTavish, J. McEwan, J. Rice, and D. Nowotnik. Vitamin-mediated targeting as a potential mechanism to increase drug uptake by tumours. J. Inorg. Biochem. 98:1625–1633 (2004).
S. H. Kim, J. H. Jeong, K. W. Chun, and T. G. Park. Target-specific cellular uptake of PLGA nanoparticles coated with poly(L-lysine)-poly(ethylene glycol)-folate conjugate. Langmuir 21:8852–8857 (2005).
Y. Hattori and Y. Maitani. Enhanced in vitro DNA transfection efficiency by novel folate-linked nanoparticles in human prostate cancer and oral cancer. J. Control. Release 97:173–183 (2004).
S. H. Pun, F. Tack, N. C. Bellocq, J. Cheng, B. H. Grubbs, G. S. Jensen, et al. Targeted delivery of RNA-cleaving DNA enzyme (DNAzyme) to tumor tissue by transferrin-modified, cyclodextrin-based particles. Cancer Biol. Ther. 3:641–650 (2004).
A. Nori and J. Kopecek. Intracellular targeting of polymer-bound drugs for cancer chemotherapy. Adv. Drug Deliv. Rev. 57:609–636 (2005).
H. Harada and S. Grant. Apoptosis regulators. Rev. Clin. Exp. Hematol. 7:117–138 (2003).
E. Vives, P. Brodin, and B. Lebleu. A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J. Biol. Chem. 272:16010–16017 (1997).
D. A. Mann and A. D. Frankel. Endocytosis and targeting of exogenous HIV-1 Tat protein. EmBO J. 10:1733–1739 (1991).
E. Kleemann, M. Neu, N. Jekel, L. Fink, T. Schmehl, T. Gessler, et al. Nano-carriers for DNA delivery to the lung based upon a TAT-derived peptide covalently coupled to PEG-PEI. J. Control. Release 109:299–316 (2005).
V. Del Gaizo, J. A. MacKenzie, and R. M. Payne. Targeting proteins to mitochondria using TAT. Mol. Genet. Metab. 80:170–180 (2003).
M. Oishi, K. Kataoka, and Y. Nagasaki. pH-responsive three-layered PEGylated polyplex micelle based on a lactosylated ABC triblock copolymer as a targetable and endosome-disruptive nonviral gene vector. Bioconjug. Chem. 17:677–688 (2006).
I. M. Hafez, N. Maurer, and P. R. Cullis. On the mechanism whereby cationic lipids promote intracellular delivery of polynucleic acids. Gene Ther. 8:1188–1196 (2001).
J. Wang, D. Mongayt, and V. P. Torchilin. Polymeric micelles for delivery of poorly soluble drugs: preparation and anticancer activity in vitro of paclitaxel incorporated into mixed micelles based on poly(ethylene glycol)-lipid conjugate and positively charged lipids. J. Drug Target. 13:73–80 (2005).
S. Mishra, P. Webster, and M. E. Davis. PEGylation significantly affects cellular uptake and intracellular trafficking of non-viral gene delivery particles. Eur. J. Cell Biol. 83:97–111 (2004).
W. Li, Z. Huang, J. A. MacKay, S. Grube, and F. C. Szoka, Jr. Low-pH-sensitive poly(ethylene glycol) (PEG)-stabilized plasmid nanolipoparticles: effects of PEG chain length, lipid composition and assembly conditions on gene delivery. J. Gene Med. 7:67–79 (2005).
R. M. Sawant, J. P. Hurley, S. Salmaso, A. Kale, E. Tolcheva, T. S. Levchenko, et al. “SMART” drug delivery systems: double-targeted pH-responsive pharmaceutical nanocarriers. Bioconjug. Chem. 17:943–949 (2006).
C. A. Fustin, C. Colard, M. Filali, P. Guillet, A. S. Duwez, M. A. Meier, et al. Tuning the hydrophilicity of gold nanoparticles templated in star block copolymers. Langmuir 22:6690–6695 (2006).
C. Hiemstra, Z. Zhong, L. Li, P. J. Dijkstra, and J. Feijen. In-Situ Formation of Biodegradable Hydrogels by Stereocomplexation of PEG-(PLLA) (8) and PEG-(PDLA) (8) Star Block Copolymers. Biomacromolecules 7:2790–2795 (2006).
T. Satomi, K. Ueno, Y. Fujita H. Kobayashi, J. Tanaka, Y. Mitamura, et al. Synthesis of ploypyridine-graft-PEG copolymer for protein repellent and stable interface. J. Nanosci. Nanotechnol. 6:1792–1796 (2006).
M. L. Forrest, A. Zhao, C. Y. Won, A. W. Malick, and G. S. Kwon. Lipophilic prodrugs of Hsp90 inhibitor geldanamycin for nanoencapsulation in poly(ethylene glycol)-b-poly(epsilon-caprolactone) micelles. J. Control. Rel. 116:139–149 (2006).
Z. Sezgin, N. Yuksel, and T. Baykara. Preparation and characterization of polymeric micelles for solubilization of poorly soluble anticancer drugs. Eur. J. Pharm. Biopharm. 64:261–268 (2006).
H. Hatakeyama, H. Akita, K. Kogure, M. Oishi, Y. Nagasaki, Y. Kihira, et al. Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid. Gene. Ther. 14:68–77 (2007).
T. Kushibiki and Y. Tabata. Preparation of poly(ethylene glycol)-introduced cationized gelatin as a non-viral gene carrier. J. Biomater. Sci. Polym. Ed. 16:1447–1461 (2005).
Y. Murakami, M. Yokohama, T. Okano, H. Nishida, Y. Tomizawa, M. Endo, et al. A novel synthetic tissue-adhesive hydrogel using a crooslinkable polymeric micelle. J. Biomed. Mater. Res. A. 80:421–427 (2006).
A. Prabhutendolkar, X. Liu, E. V. Mathias, Y. Ba, and J. A. Kornfield. Synthesis of Chlorambucil-Tempol Adduct and its Delivery using Fluoroalkyl Double-Ended Poly (Ethylene Glycol) Micelles. Drug. Deliv. 13:433–440 (2006).
L. Jongpaiboonkit, Z. Zhou, X. Ni, Y. Z. Wang, and J. Li. Self-association and micelle formation of biodegredable poly(ethylene glycol)-poly(L-lactid acid) amphiphilic di-block co-polymers. J. Biomater. Sci. Polym. Ed. 17:747–763 (2006).
T. G. Park and H. S. Yoo. Dexamethasone nano-aggregates composed of PEG-PLA-PEG triblock copolymers for anti-proliferation of smooth muscle cells. Int. J. Pharm. 326:169–173 (2006).
Y. Bae, W. D. Jang, N. Nishiyama, S. Fukushima, and K. Kataoka. Multifunctional polymeric micelles with folate-mediated cancer cell targeting and pH-triggered drug releasing properties for active intracellular drug delivery. Mol. Biosyst. 1:242–250 (2005).
M. O. Oyewumi, R. A. Yokel, M. Jay, T. Coakley, and R. J. Mumper. Comparison of cell uptake, biodistribution, and tumor retention of folate-coated and PEG-coated gadolinium nanoparticles in tumor bearing mice. J. Control. Rel. 95:613–626 (2004).
S. Kubetzko, E. Balic, R. Waibel, U. Zangemeister-Wittke, and A. Pluckthun. PEGylation and Multimerization of the Anti-p185-HER-2 single-chain Fv fragment 4D5: Effects on tumor targeting. J. Biol. Chem. 281:35186–35201 (2006).
D. C. Bibby, J. E. Talmadge, M. K. Dalal, S. G. Kurz, K. M. Chytil, S. E. Barry, et al. Phrmacokinetics and biodistribution of RGD-targeted doxorubicin-loaded nanoparticles in tumor-bearing mice. Int. J. Pharm. 293:281–290 (2005).
S. Utreja, A. J. Khopade, and N. K. Jain. Lipoprotein-mimicking biovectorized systems for methotrexate delivery. Pharm. Acta. Helv. 73:275–279 (1999).
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van Vlerken, L.E., Vyas, T.K. & Amiji, M.M. Poly(ethylene glycol)-modified Nanocarriers for Tumor-targeted and Intracellular Delivery. Pharm Res 24, 1405–1414 (2007). https://doi.org/10.1007/s11095-007-9284-6
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DOI: https://doi.org/10.1007/s11095-007-9284-6