Supramolecular Copolymer Micelles Based on the Complementary Multiple Hydrogen

Bonds of Nucleobases for Drug

Delievery

Wang D. et al

Presented by Sunita Sharma 1/30/2012

Background
Main Cancer Treatments
Surgery
Invasive and only effective in stage I and II cancer treatment.

Block Copolymer Micelles

Improve solubility and bioavailability of hydrophobic drugs in water. Size allows prolong drug circulation time after administration Programmable delivery system which the release of drugs can be controlled via pH of environment.

Radiation therapy
Can possibly damage normal tissue and organs near the tumor

Chemotherapy
Drugs only present in the body for a limited time period

Main paper objective based upon the finding that rapid drug release will reduce drug resistance in cells.

Supramolecular Polymers
Supramolecular polymer is a polymer whose monomer repeat units are held together by non-covalent bonds, like co-ordination, pi-pi interaction and hydrogen bonding. In this article, two polymers have been used to assemble is supramolecular polymer PCL-A and PEG-U

Purpose and method

Synthesis of PCL-A and U-PEG Synthesis of PCL-A:U-PEG micelles

Insure pH-Triggered DOX Release

Cell Internalization and DOX Release

Synthesis and Characterization of PCL-A

Synthesis and Characterization of U-PEG

Figure 2. Gel permeation chromatography (GPC) curves of adenineterminated poly(-caprolactone) (PCL-A): (A) PCL25-A, (B) PCL40-A, (C) PCL49-A.

Table 1. Characterization of Adenine-Terminated Poly(-caprolactone) (PCL-A) Polymers

polymers PCL-A 1 2 3
a 1

Synthesis of PCL-A:U-PEG micelles

Mna ( 1H NMR) 2800 3600 4500
b

Figure 3. 1H NMR NH and NH2 chemical shifts of the adenineterminated poly(-caprolactone) (PCL-A) and uracil-terminated poly(ethylene glycol) (PEG-U) complex (1:1) asafunction of temperature. Sample wasallowed to equilibrate for 10 min at each temperature (400 MHz, 1,1,2,2-tetrachloroethane-d2).

Mnb (GPC) 2870 4590 5630

Mwb (GPC) 2890 4950 6470

PDI b (GPC) 1.01 1.08 1.15

Table 2. Properties of the PCL-A:U-PEG Micelles

sample PCL25-A:U-PEG114 PCL40-A:U-PEG114 PCL49-A:U-PEG114
a

CMCa (mg/ mL) 6.5 3.9 1.8 10 10 10

2 2 2

diameterb (nm) 142 156 172

PDI b 0.097 0.093 0.139

Determined by H NMR. Determined by gel permeation chromatography/ multiangle laser light scattering (GPC-MALLS) usingTHF as the eluent.

bonds.41,42 However, assoon asthesample iscooled from 100 to 25C,theNH resonancereturnstoitsoriginal position at 8.7ppm. S imilarly, theNH2 resonanceexhibitsthesamechangein therange of 5.74 5.35 ppm. All of these data suggest that complementary hydrogen bonds generate between PCL-A and PEG-U, and the supramolecular diblock copolymersarethermoreversiblein1,1,2,2tetrachloroethane-d2. To further evaluate the hydrogen bonding interactions between PCL-A and PEG-U, FTIR was performed at various temperatures (from 25 to 160 C). Figure S2 shows the partial IRspectraof PCL-A and PEG-U complexesin thebulk state.The bands between 1750 and 1710 cm 1 come from the Cd O stretching vibration. It can be found that the Cd O stretching peak shifts to higher frequency from 1724 to 1734 cm 1 as the temperatureraisesfrom 25to 160C. When thesampleiscooled from 160 to 25 C, the Cd O stretching peak returns to its original position at 1724 cm 1. According to previousliterature, the Cd O stretching bands shift to lower frequencies upon hydrogen bond formation.43 It is concluded that the comple-

Critical micelle concentration (CMC) was determined by UV/ vis spectrometer. bDiameter and polydispersity index (PDI) of PCL-A:UPEG micelles were determined by dynamic light scattering (DLS).

U-PEG block copolymers were prepared by dialysis method and the resulting micelles had a yield of 92% (weight of resulting micelles/ weight of copolymers in feed). The CMC of these supramolecular copolymers were investigated by UV/ vis spectra using DPH as a hydrophobic probe. The relationship of the content of PCL with theCMC islisted in Table2. Asthecontent of PCL in copolymersincreases, the CMC gradually decreases. To further study the properties of supramolecular copolymer micelles, both DLS and TEM measurements were performed. DLSresults show that all of the PCL-A:U-PEG micelles exhibit unimodal size distribution with the mean diameter from 142 to 172 nm and the detailed data are summarized in Table 2. Apparently, the average diameter of the micelles increases as the PCL increases from Mn = 2.8 k to Mn = 5.6 k with the same PEG block. Thisindicatesthat along PCL block can enhance its assembly and lead to a large core. The morphologies of supramolecular copolymer micellesfor PCL49-A:U-PEG114 visualized

Insure pH-Triggered DOX Release

Cell Internalization and DOX Release

Conclusion
Successful development of stimuli responsive micelles, self assembled from PCL-A:U-PEG

These micelles strongly respond to mild acidic pH and release the drug inside the shell, leading to increased drug efficacy Stimuli responsive micelles are promising candidates for improvements in drug delivery systems.

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Reference
Wang, D.; Su, Y.; Jin, C.; Zhu, B.; Pang, Y.; Zhu, P.; Liu, J.; Tu, C.; Yan, D.; Zhu, X. Biomacromolecules 2011, 12, 1370-1379.
Toncheva, V.; Schacht, E.; Ng, S. y.; Barr, J.; Heller, J. J. Drug Targeting 2003, 11, 345-353.