WO2001087227A2 - Drug containing polymeric micelles - Google Patents
Drug containing polymeric micelles Download PDFInfo
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- WO2001087227A2 WO2001087227A2 PCT/IB2001/001456 IB0101456W WO0187227A2 WO 2001087227 A2 WO2001087227 A2 WO 2001087227A2 IB 0101456 W IB0101456 W IB 0101456W WO 0187227 A2 WO0187227 A2 WO 0187227A2
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- DDAHBPFLOUFUBI-QUFPSDLASA-N C[C@@H]1C(C)C=C[C@H]1C Chemical compound C[C@@H]1C(C)C=C[C@H]1C DDAHBPFLOUFUBI-QUFPSDLASA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- compositions comprising polymeric micelles which are useful for improving the potency of therapeutic agents, including, but not limited to, anticancer drugs.
- a major obstacle associated with the use of chemotherapeutic agents is the lack of selectivity towards cancerous cells. This lack of selectivity has been linked to the toxic side effects of the use of such agents due to their delivery to both normal and abnormal cells. Lack of selectivity of drugs towards target cells is also a problem in the treatment of a variety of disorders in addition to cancer.
- Much research effort has focused on development of carriers for drugs that can selectively deliver the drug to target cells. For example, in order to improve the specific delivery of drugs with low therapeutic index, several drug carriers such as liposomes, microparticles, nano-associates and drug-polymer conjugates have been studied.
- liposomes phospholipid vesicles
- Their targeting efficacy is, however, limited by quick scavenging by reticuloendothelial (RE) cells of the liver and spleen, instability in the plasma, limited capability at extravasation due to size, technical problems with their production and susceptibility to oxidation. Solutions to individual problems have been found, but a solution to more • than one problem has never been combined in a single composition. For example, if recognition by RE cells is reduced and stability improved, it is very difficult to obtain liposomes having a diameter of less than 50 n . Alternative methods at improving the targeting potential have been investigated.
- pH sensitive liposomes Such methods have included temperature sensitive liposomes, magnetic liposomes and pH sensitive liposomes.
- the rationale underlying the use of pH sensitive liposomes lies in the observation that the pH in tumoral tissue is lower than normal, and therefore the local concentration of drug could be increased since the liposomes would release their contents inside the tumor more readily than in other tissues.
- Another possibility would be that the liposomes would be destabilised after having penetrated the cells since the endosomes in which they end up following endocytosis is in itself acidic.
- Polymeric micelles were first proposed as drug carriers by Bader, H. et al in 1984. Angew. Makromol . Chem. 123/124 (1984) 457-485. Polymeric micelles have been the object of growing scientific attention, and have emerged as a potential carrier for drugs having poor water solubility because they can solubilize those drugs in their inner core and they offer attractive characteristics such as a generally small size ( ⁇ 100nm) and a propensity to evade scavenging by the reticuloendothelial system (RE) .
- RE reticuloendothelial system
- Micelles are often compared to naturally occurring carriers such as viruses or lipoproteins . All three of these carriers demonstrate a similar core-shell structure that allows for their contents to be protected during transportation to the target cell, whether it is DNA for viruses or water-insoluble drugs for lipoproteins and micelles .
- Lipoproteins were proposed as a vehicle for the
- viral carriers are mainly used for the delivery of genetic material and may have optimal use in applications that do not require repeated application of the delivery vehicle, since they are likely to elicit an immune response.
- Polymeric micelles seem to be one of the most advantageous carriers for the delivery of water-insoluble drugs.
- Polymeric micelles are characterized by a core-shell structure.
- Pharmaceutical research on polymeric micelles has been mainly focused on copolymers having an A-B diblock structure with A, the hydrophilic shell moieties and B the hydrophobic core polymers, respectively.
- Multiblock copolymers such as poly (ethylene oxide) -poly (propylene oxide)- poly (ethylene oxide) (PEO-PPO-PEO) (A-B-A) can also self-organize into micelles, and have been described as 5 potential drug carriers. Kabanov, A.V. et al , FEBS Lett. 258
- the hydrophobic core which generally consists of a biodegradable polymer such as a pol ( ⁇ -benzyl-
- PBLA L-aspartate
- PLLA poly (DL-lactic acid)
- PCL ( ⁇ -caprolactone)
- the core may also consist of a water-soluble polymer, such as poly (aspartic acid) (P(Asp)), which is rendered hydrophobic by the chemical conjugation of a hydrophobic drug, or is formed through the association of two 35 oppositely charged polyions (polyion complex micelles) .
- P(Asp) poly (aspartic acid)
- PMMA poly (methyl methacrylate)
- the hydrophobic inner core can also consist of a highly hydrophobic small chain such as an alkyl chain or a diacyllipid such as distearoyl phosphatidyl ethanolamine (DSPE) .
- the hydrophobic chain can be either attached to one end of a polymer, or randomly distributed within the polymeric structure.
- the shell is responsible for micelle stabilization and interactions with plasmatic proteins and cell membranes. It usually consists of chains of hydrophilic, non-biodegradable, biocompatible polymers such as PEO. The biodistribution of the carrier is mainly dictated by the nature of the hydrophilic shell. Other polymers such as poly (N- isopropylacrylamide) (PNIPA) and poly (alkylacrylic acid) impart temperature or pH sensitivity to the micelles, and could eventually be used to confer bioadhesive properties.
- PNIPA poly (N- isopropylacrylamide)
- alkylacrylic acid impart temperature or pH sensitivity to the micelles, and could eventually be used to confer bioadhesive properties.
- Micelles presenting functional groups at their surface for conjugation with a targeting moiety are also known. See, e.g., Scholz, C. et al , Macromolecules 28 (1995) 7295-7297.
- Photodynamic therapy is a site-specific alternative to radio- and chemotherapy of solid malignancies which involves illumination of the lesions with visible light after systemic administration of a tumor-localizing photosensitizer . This results in the photooxidation of biomolecules, leading to microvascular stasis or direct tumor cell kill and, finally, to tumor necrosis and, eventually, tumor cure.
- Photooxidation of biomolecules leading to microvascular stasis or direct tumor cell kill and, finally, to tumor necrosis and, eventually, tumor cure.
- the metallo-phthalocyanines have been studied extensively. See, e . g. , Spikes, J.E., Photochem. Photobiol . 1986, 43, 691-699; Rosenthal, I., Photochem. Photobiol. 1991, 53, 859-870.
- AlClPc unsubstituted aluminum chloride phthalocyanine
- the present invention provides novel polymeric micelles which are pH-sensitive and optionally may also be temperature-sensitive, and which may be used to formulate therapeutic agents, including photosensitizer agents in aqueous solutions.
- the present invention provides a micelle-forming composition, comprising: a therapeutic agent; and a polymer which comprises at least one hydrophilic moiety, a pH-sensitive moiety and a hydrophobic moiety, wherein said micelle comprises a hydrophobic core surrounded by a hydrophilic shell, and wherein said therapeutic agent is contained within said micelle.
- the present invention further provides methods for loading the polymeric micelles with at least one suitable therapeutic agent .
- the present invention also provides a polymeric micelle composition, comprising a therapeutic agent, wherein the therapeutic agent is protected from chemical interactions, such as hydrolysis, by being contained within the hydrophobic core of said micelle.
- the present invention provides a colloidal composition consisting of polymeric micelles which may be used to deliver therapeutic agents which have poor water solubility.
- the polymeric micelles are characterized by a core shell structure, wherein a hydrophobic core is surrounded by a hydrophilic shell.
- the hydrophilic shell comprises a hydrophilic polymer or copolymer and a pH sensitive component .
- the hydrophilic polymer or copolymer is preferably a compound which exhibits a lower critical solution temperature (LCST) between 30°C and 45°C.
- Preferred hydrophilic polymers or copolymers include, but are not limited to, poly (N- substituted acrylamides) , poly (N-acryloyl pyrrolidine) , poly (N-acryloyl piperidine) , poly (N-acryl-L-amino acid amides) , poly (ethyl oxazoline) , methylcellulose, hydroxypropyl acrylate, hydroxyalkyl cellulose derivatives and poly (vinyl alcohol), poly (N-isopropylacrylamide) , poly (N-vinyl-2 -pyrrolidone) , polyethyleneglycol derivatives, and combinations thereof.
- a particularly preferred hydrophilic polymer is poly (N-isopropylacrylamide) and its copolymers with N-vinyl-2 -pyrrolidone .
- the second component of the hydrophilic shell is an ionizable, pH-sensitive moiety.
- the pH-sensitive moiety is an alkylacrylic acid, including, but not limited to methacrylic acid, ethylacrylic acid, propyl acrylic acid and butyl acrylic acid, or an amino acid such as glutamic acid.
- the pH-sensitive moiety is utilized at a level of up to about 10 mol% of the polymeric micelle. When using methacrylic acid satisfactory results can be obtained using between about 2 mol% and about 5 mol%.
- the hydrophobic moiety constitutes the core of the micelle. It may consist of a single alkyl chain, such as octadecyl acrylate or a double chain alkyl compound such as phosphatidylethanolamine or dioctadecylamine .
- the hydrophobic moiety may also be a water insoluble polymer such as a poly (lactic acid) or a poly (e—caprolactone) .
- the hydrophobic moiety is selected so as to have a mass of up to 10 kDa. It can be randomly distributed in the hydrophilic polymeric chain or attached to one end of the polymer. When the hydrophobic moiety is an alkyl chain, it should be present at a concentration varying between about lmol% and about 5 mol%.
- Polymeric micelles exhibiting pH-sensitive properties may also be formed by using common pH-sensitive polymers including, but not limited to copolymers from methacrylic acid, methacrylic acid esters and acrylic acid esters, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate and cellulose acetate trimellitate . As stated above, in order to form micelles these polymers need to contain a hydrophobic moiety.
- Micelle formation occurs as a result of two forces. One is an attractive force that leads to the association of molecules, while the other is a repulsive force that prevents unlimited growth of the micelles to a distinct macroscopic phase.
- Amphiphilic copolymers self-associate when placed in a solvent that is selective for either the hydrophilic or hydrophobic polymer.
- micellization process of amphiphilic copolymers is similar to that for low molecular weight surfactants.
- the polymers exist only as single chains.
- CAC critical association concentration
- polymer chains start to associate to form micelles in such a way that the hydrophobic part of the copolymer will avoid contact with the aqueous media in which the polymer is diluted.
- an important quantity of solvent can be found inside the micellar core, and micelles are described as loose aggregates which exhibit larger size than micelles formed at higher concentrations.
- Amphiphilic copolymers usually exhibit a CAC which is much lower than that of low molecular weight surfactants.
- the CAC of PEO-PBLA and PNIPA-PSt are between 0.0005-0.002%.
- CAC reaching up to 0.01-10% in the case of poloxamers .
- Amphiphilic copolymers with high CAC may not be suitable as drug targeting devices since they are unstable in an aqueous environment and are easily dissociated upon dilution.
- micellization of amphiphilic copolymers can result m• two different types of micelles depending on whether the hydrophobic chain is randomly bound to the hydrophilic polymer or grafted to one end of the hydrophilic chain.
- Micelles formed from randomly modified polymers are smaller than end-modified polymers.
- the micellar size is mainly determined by the hydrophobic forces which sequester the hydrophobic chains in the core, and by the excluded volume repulsion between the chains which limits their size. The difference in the balance of these two forces in random and end-modified copolymers may account for their different size.
- CAC Critical Association Concentration
- a preferred method to determine the CAC involves the use of fluorescent probes, among which pyrene is the most widely used.
- Pyrene is a condensed aromatic hydrocarbon that is highly hydrophobic and sensitive to the polarity of the surrounding environment. Below the CAC, pyrene is solubilized in water, a medium of high polarity. When micelles are formed, pyrene partitions preferentially toward the hydrophobic domain afforded by the micellar core, and thus experiences a non-polar environment. Consequently, numerous changes such as an increase in the fluorescence intensity, a change in the vibrational fine structure of the emission spectra, and a red shift of the (0,0) band in the excitation spectra are observed.
- the apparent CAC can be obtained from the plot of the fluorescence of pyrene, the
- I x /I 3 ratio from emission spectra or the I 333 /l 33a ratio from the excitation spectra versus concentration.
- a major change in the slope indicates the onset of micellization.
- the 1 x /l- 3 ratio is the intensity ratio between the first and third highest energy emission peaks and is measured at a constant excitation wavelength and variable emission wavelengths corresponding to I x and I 3 .
- the CAC determined with fluorescence techniques needs to be carefully interpreted for two reasons. First, the concentration of pyrene should be kept extremely low (10 "7 M) , so that a change in slope can be precisely detected as micellization occurs.
- Polymeric micelles such as those of the compositions of the invention are characterized by their small size (10- lOOnm) . Besides being needed for extravasation of the carrier materials, this small size permits the sterilization of the composition to be effected simply by filtration, and minimizes the risks of embolism in capillaries. This is not the situation encountered with larger drug carriers.
- Micellar size depends on several factors including copolymer molecular weight, relative proportion of hydrophilic and hydrophobic chains and aggregation number. The size of micelles prepared by dialysis can be affected by the organic solvent used to dissolve the polymer.
- LCST critical solution temperature
- Micellar diameter and size polydispersity can be obtained directly in water or in an isotonic buffer by dynamic light scattering (DLS) .
- DLS can also provide information on the sphericity of polymeric micelles. Using DLS it was shown that the addition of a low molecular weight surfactant such as sodium dodecyl sulfate (1% w/v) can destroy the polymeric micelle structure and bring about a complete shift of the mean diameter from approximately 50 to 3nm.
- a low molecular weight surfactant such as sodium dodecyl sulfate (1% w/v) can destroy the polymeric micelle structure and bring about a complete shift of the mean diameter from approximately 50 to 3nm.
- Micellar size can also be estimated by methods such as atomic force microscopy (AFM) , transmission electron microscopy (TEM) and scanning electron microscopy (SEM) . These methods allow the characterization of the micelle shape and size dispersity. Ultracentrifugation velocity studies are sometimes performed to assess the polydispersity of polymeric micelles.
- AFM atomic force microscopy
- TEM transmission electron microscopy
- SEM scanning electron microscopy
- Loading of a therapeutic agent into the micelles can be realized according to techniques well known to one skilled in the art. For example, loading may be effected by dissolution of the compound in a solution containing preformed micelles, by the oil-in-water procedure or the dialysis method.
- Therapeutic agents which may be used are any compounds, including the ones listed below, which can be entrapped, in a stable manner, in polymeric micelles and administered at a therapeutically effective dose.
- the therapeutic agents used in accordance with the invention are hydrophobic in order to be efficiently loaded into the micelles.
- Suitable drugs include antitumor compounds such as phthalocyanines (e.g. aluminum chloride phthalocyanine), anthracyclines (e.g. doxorubicin) , poorly soluble antimetabolites (e.g. methotrexate, mitomycin, 5- fluorouracil) and alkylating agents (e.g. carmustine) .
- Micelles may also contain taxanes such as paclitaxel.
- Additional drugs which can be contained in micelles are conventional hydrophobic antibiotics and antifungal agents such as amphotericin B, poorly water soluble immunomodulators such as cyclosporin, poorly water soluble antiviral drugs such as HIV protease inhibitors and poorly water-soluble steroidal (e.g. dexamethasone) , non-steroidal (e.g. indomethacin) anti-inflammatory drugs and genome fragments with or without a carrier.
- conventional hydrophobic antibiotics and antifungal agents such as amphotericin B
- poorly water soluble immunomodulators such as cyclosporin
- poorly water soluble antiviral drugs such as HIV protease inhibitors and poorly water-soluble steroidal (e.g. dexamethasone)
- non-steroidal (e.g. indomethacin) anti-inflammatory drugs and genome fragments with or without a carrier e.g. indomethacin
- drugs can be incorporated into the polymeric micelle compositions of the invention by means of chemical conjugation or by physical entrapment through dialysis or emulsification techniques.
- the simple equilibration of the drug and micelles in water may not result in high levels of incorporated drug.
- Chemical conjugation implies the formation of a covalent bond, such as an amide bond, between specific groups on the drug and the hydrophobic polymer of the core. Such bonds are resistant to enzymatic cleavage mainly because of steric hindrance, and cannot be readily hydrolyzed unless spacer groups are introduced.
- the therapeutic agent is incorporated by a physical entrapment procedure .
- Hydrophilic compounds such as proteins may also be incorporated in the polymeric micelle compositions of the invention.
- the incorporation of such hydrophilic species may, however, require the chemical hydrophobization of the molecule .
- Polyionic compounds can be incorporated through the formation of polyionic complex micelles.
- the dialysis method consists in bringing the drug and copolymer from a solvent in which they are both soluble, such as ethanol or
- N / N-dimethylformamide to a solvent that is selective only for the hydrophilic part of the polymer, such as water.
- a solvent that is selective only for the hydrophilic part of the polymer such as water.
- the hydrophobic portion of the polymer associates to form the micellar core incorporating the insoluble drug during the process.
- Complete removal of the organic solvent may be brought about by extending the dialysis over several days.
- a solution of the drug in a water-insoluble volatile solvent, such as chloroform is added to an aqueous solution of the copolymer to form an oil- in-water emulsion.
- the micelle-drug conjugate is formed as the solvent evaporates.
- the main advantage of the dialysis procedure over the latter method is that the use of potentially toxic solvents such as chlorinated solvents can be avoided.
- Both dialysis and oil-in-water emulsion methods were compared for the incorporation of DOX in PEO-PBLA micelles.
- the emulsification method was more efficient since the DOX content of the micelles was estimated to be 12% ( w/w) compared to 8% (w/w) for the dialysis technique.
- the drug loading procedure may affect the distribution of a drug within the micelle.
- "Cao et al . (Macromolecules 24 (1991) 6300-6305) , showed that pyrene incorporated in micelles as they were forming was not protected from the aqueous environment as well as pyrene incorporated after micelles were formed, although the first method yielded a drug loading three times higher than the second method.
- Entrapment efficiency of the polymeric micelles of the invention depends on the initial amount of drug added. Exceeding the maximum loading capacity results in precipitation of the therapeutic agent, and consequently, lower yield. Further, efficiency of loading of the therapeutic agent depends on the aggregation number of copolymer. Micelles showing a higher aggregation number allow a greater amount of drug to be solubilized in their inner core .
- polymeric micelle compositions of the invention are believed to be suitable for use as delivery systems for a wide range of therapeutic agents, including, but not limited to, anticancer drugs, plasmid DNA, antisense oligonucleotides or for the delivery of diagnostic agents to a specific organ in the body.
- therapeutic agents including, but not limited to, anticancer drugs, plasmid DNA, antisense oligonucleotides or for the delivery of diagnostic agents to a specific organ in the body.
- the polymeric micelle compositions of the invention are suitable for use in a variety of pharmaceutical fields, such as oral delivery, sustained release and site-specific drug targeting.
- the micelles of the invention are used as a transport for water- insoluble drugs.
- micelles of the invention when used to transport an anticancer drug to malignant tumor cells, elicit a dramatic increase of the potency of the drug.
- polymeric micelles may enter cells via the endocytic pathway. Release of drugs in the endosomes may prevent inactivation of the drug in the lysosomes . It is further believed that pH sensitive micelles may destabilise the endosomal membrane and provoke an intercellular distribution of the drug that is favorable to its pharmacological activity.
- NIPA N-isopropylacrylamide
- MAA octadecyl acrylate
- ODA octadecyl acrylate
- AIBN 2-2'- azobisisobutyronitrile
- Optical grade pyrene was purchased from Aldrich and used as received. All other chemicals were of analytical grade and used as received. 1 , 2-propanediol and CRM (polyethoxylated castor oil) were purchased from Sigma (St. Louis, MO) .
- Copolymer compositions were determined by X H NMR spectrometry and titration. H NMR spectra were recorded on a Bruker AMX600 spectrometer in CDCl 3 -deuterated chloroform solutions 5 at 25°C with a relaxation time of 10 s. The MAA content of copolymer was assayed by titration.
- CAC Determination of CAC.
- CAC was determined in both water and phosphate-buffered saline (PBS) .
- PBS phosphate-buffered saline
- the polymeric solution in PBS was prepared each time by first dissolving the polymer in water. Fluorescence measurements were made after 5 min. under stirring at 20°C. The excitation wavelength was fixed at 336 nm. The values of
- micellar core 20 micellar core and experiences a non-polar environment which results in a decrease of the I ⁇ /I 3 ratio.
- Phase transition pH A polymeric solution in ethanol was prepared and then dissolved in PBS or phosphate buffer 67 mM.
- Size measurements were performed by photon correlation spectroscopy (PCS) using a Coulter N4 Plus (Hialeah, FL) in several media, namely, water, PBS, non-isotonic phosphate buffer 67 mM (pH 7.4), dextrose 5% (w/v) and isotonic saline solution (NaCl 0.9%, w/v) .
- Micellar sizes were estimated at 62.6° or 90° scattering angle, before and after filtration through a 0.22- ⁇ m pore-size filter at 20°C and 37°C. Micellar size was measured for polymer containing 2 or 4 mol% ODA.
- the micelles were prepared by dissolving the polymer in an organic solvent. Polymeric solutions in ethanol , N, N- dimethylformamide (DMF) or THF were prepared, then dialyzed against water for 24 h using a Spectra/Por membrane MWCO 6- 8000 (Spectrum Laboratories, Inc., Madison Hills, CA) . The stability of poly (NIPA- co-MAA-co-ODA) was also evaluated by measuring the variation of micellar size in water, phosphate buffer and PBS over a 2 -month period. All samples were stored at 4°C.
- Electrophoretic mobility of the particles was determined by Laser-Doppler anemometry electrophoresis with a Coulter Delsa 440SX (Miami, FL) and transformed into zeta potential by applying the Smoluchowski equation. Duplicate measurements were performed in PBS and 10 mM NaCl, at 23 °C.
- DL amount of drug in micelle xlOO Eq 2. amount of micelles Cellular photoinactivation.
- Stock solutions of AlClPc-loaded PM (ALCLPc-PM) in dextrose 5% (w/v) and AlClPc in PBS containing 10% ( v/v) CRM EL and 3% (v/v) 1 , 2-propanediol (AlClPc CRM) were prepared and filtered on a 0.22- ⁇ m filter. The solutions were then diluted to the desired concentration with Waymouth's medium (Gibco, Burlington, Canada) containing 1% fetal bovine serum (FBS) (ICN, Aurora, OH) .
- Waymouth's medium Gibco, Burlington, Canada
- FBS fetal bovine serum
- EMT-6 mouse mammary tumor cells were maintained in Waymouth's medium supplemented with 15% FBS and 1% L-glutamin (Gibco) .
- Cell survival was estimated by means of the colorimetric MTT (3- (4-5-dimethylthiazol-2-yl) -2 , 5-diphenyltetrazolium bromide) assay. Briefly, 15 x 10 3 EMT-6 cells per well were inoculated in 100 ⁇ L Waymouth's growth medium in 96 multi- well plates and incubated overnight at 37°C and 5% C0 2 .
- the cells were rinsed twice with PBS and incubated with 100 ⁇ L of the drug (AlClPc CRM or AlClPc PM) at various concentrations in Waymouth's medium containing 1% FBS for 1 or 24 h at 37°C and 5% C0 2 . After incubation, the cells were rinsed twice with PBS, refed with 100 ⁇ L Waymouth's medium and exposed to red light.
- the light source consisted of 2 500-W tungsten/halogen lamps (GTE Sylvania, Montreal, Canada) fitted with a circulating, refrigerated, aqueous Rhodamine filter.
- the fluence rate calculated over the absorbance peak of AlClPc was 10 mW cm “2 , and the plates were illuminated for 10 min for a total fluence of 6 Jem "2 .
- the cells were incubated overnight at 37°C and 5% C0 2 before assessing cell viability.
- Fifty ⁇ L of a 5-fold diluted MTT stock solution (Aldrich, Milwaukee, WS ; 5 mg/mL PBS) in Waymouth's medium was added to each well. After 3 h, 100 ⁇ L sodium dodecyl sulphate (Gibco) 10% in 0.01 N HCl was added in the wells.
- the plates were incubated overnight at 37°C, after which absorbance was read at 570 nm by means of a microplate reader (Molecular Devices, Thermo Max, Sunnyvale, CA) . Average absorbance of the blank wells in which cells were omitted was subtracted from the readings of the other wells. Average absorbance of the control cells, which were incubated with dye-free Waymouth's 1% FBS, represents 100% cell survival. The extracellular drug dose required to inactivate 90% of cells (LD 90 ) was extrapolated from the survival curves. Eight-fold replicates were run peer drug and light dose, and each experiment was repeated at least 3 times.
- the proportion of ODA was obtained by comparing the signals at 4.03 ppm of the proton H B (NIPA) and 0.89 ppm of the proton H B (ODA) . It was found that the ODA content of poly (NIPA 93 -co-MAA 5 -co-ODA 2 ) and poly(NIPA 91 -co-MAA 5 -co-ODA 4 ) was 3.1 and 6.2 mol%, respectively.
- CAC Determination of CAC.
- the apparent CAC was determined from the intersection of straight line segments drawn through points corresponding to the lowest polymer concentrations which lie on a nearly horizontal line with that going through the points on the rapidly-rising part of the plot.
- the value of the apparent CAC was found to be near 10 mg/L for polymers containing either 2 or 4 mol% ODA, whether the medium was water or PBS (Fig. 2) .
- the ratio 1 ⁇ /1 ⁇ remains fairly constant, confirming the absence of micelles (Fig. 2A) .
- the CAC was not different in water and PBS, indicating that it is not affected by the presence of salts.
- Phase transition pH Poly is a thermo-responsive polymer which exhibits a lower critical solution temperature (LCST) of 32°C. At temperatures under the LCST, the polymer is soluble but precipitates if the temperature is raised above the LCST.
- LCST critical solution temperature
- MAA hydrophilic titrable monomer
- the polymer then becomes soluble at body temperature (37°C) but precipitates as the pH decreases.
- the polymer undergoes phase transition at a pH of 5.7-5.8 at 37°C.
- the presence of 2 or 4 mol% of ODA does not seem to affect phase transition pH, since it remains similar in both cases and comparable to the phase transition pH of the copolymer without ODA (Fig. 3C) .
- poly (N PA 91 - co-MAA 5 - co-ODA 4 ) micelles were prepared by the dialysis method. In water at 20°C, after filtration, the measured micelle diameters were 10 and 14 nm for micelles prepared with DMF and THF, respectively. However, when prepared in ethanol, micelles had a diameter of over 400 nm. For poly (NIPA 93 -co-MAA 5 -co-ODA 2 ) , the size of poly (NIPA 91 -co-MAA 5 - co-ODA 4 ) micelles was dependent on the nature of the aqueous medium.
- pH-sensitive PM could be prepared from hydrophobically-modified poly (NIPA) by adding hydrophilic titrable monomers, such as MAA.
- the polymer exhibits a low CAC as well as an acidic phase transition pH.
- PM made from the polymer containing 2 mol% ODA and 5 mol% MAA showed adequate water solubility and could be loaded with a substantial amount of the photoactive compound AlClPc.
- the PM formulation induced a greater degree of cellular photoinactivation than the CRM preparation. Without being bound by theory, it is believed that the pH-sensitive micelles of the invention can modify the intracellular distribution of the drug, thereby increasing its potency.
- Disuccinimidyl 4 , 4 ' -azobis (4-cyoanovalerate) (A-501) was prepared by mixing 4 , 4 ' -azobis (4-cyoanovaleric acid) (V-501) with 1.25 equivalents of N-hydroxysuccinimide in the presence of 1.5 equivalents of l-ethyl-3- [3- (dimethylamino) - propyl] carbodiimide hydrochloride (EDC) in dry THF/CH 3 CN
- the lipophilic radical initiator DODA-501 was prepared by the reaction of dioctadecylamine (recrystallized from acetone before use) with 0.8 equiv of A-501 in dry THF/CHC1 3
- NIPA N-isopropylacrylamide
- DODA-poly (NIPA -co-MAA) was prepared by mixing NIPA, MAA and DODA-501 at a molar ratio of 96 :3 :1 (NIPA:lg, MAA:24 ⁇ L, DODA-501 : 0.0592g) in 40 mL of anhydrous 1,4-dioxane. The solution was degassed by bubbling N 2 for 15 min and then heated at 69°C overnight. Polymer was recovered by several reprecipitations from diethylether, after solubilization in tetrahydrofuran (THF) . After filtration, the polymer was dissolved in water and dialysed against water for 48h (MWCO 6000-8000, Spectrum Laboratories, Website, CA) . The suspension was filtered on 0.2 ⁇ m Nylon filter and then freeze-dried for 48h.
- NIPA 1,4-dioxane
- the weight (Mw) and number-average (Mn) molecular weights of the polymer were determined by gel permeation chromatography in THF, using polystyrene standards for calibration. Mw and Mn were respectively 18000 and 8000 and the polydispersity index was 2.08.
- Copolymer composition was determined by 1 H NMR spectrometry and titration
- the percentage of MAA was determined by acid-base titration of an ethanol polymer solution (1.6 mg/mL) .
- the MAA content determined by titration was 4.6 mol% MAA.
- the proportion of DODA was measured, by comparing the integration after deconvolution of the proton signal of NIPA (1.1 ppm) and the proton signal of DODA (0.9 ppm) . It was found that the DODA content of DODA- L - poly (NIPA 96 -co-MAA 3 ) was 1.1 mol% DODA.
- phase transition pH of the polymer was determined by light scattering (480 nm) at 37°C using a Series 2 Aminco Bowman fluorimeter (Spectronics Instruments Inc., Rochester, NY) . A polymeric solution in ethanol was prepared and then dissolved in PBS (25 mg/L) . Measurements were taken after 5 min (in water, with stirring, at 37°C) . The resulting intensities were plotted as a function of pH. Phase transition pH was determined from the intersection of a straight line going through points on the rapidly-rising part of the plot and the abscissa axis. The copolymer DODA- L - poly (NIPAgg- co-MAA 3 ) starts to precipitate at pH 6.
- the critical association concentration (CAC) of the copolymers was determined by a steady-state pyrene fluorescence method. Several polymeric solutions in water differing in polymer concentration but each containing 10 ⁇ 7 M pyrene were prepared and kept stirred overnight in the dark. Steady-state fluorescent spectra were measured ( at 390 nm) after 5 min under stirring at 20°C using a Series 2 Aminco Bowman fluorimeter (Spectronics Instruments Inc., Rochester, NY) . The value of the CAC of the copolymer DODA- L -poly (NIPA 9S - co-MAA 3 ) was 33 mg/L.
- micellar size was measured after filtration through a 0.22- ⁇ m pore-size filter.
- micelle size of the copolymer DODA 1 -poly(NIPA 96 -co-MAA 3 ) presented a bimodal distribution, with a small particle population of approximately 35 nm and larger aggregates around 100 nm.
- the lipophilic radical initiator DODA-501 was prepared as described in section A.
- the NIPA and MAA were purified with the method described in section A.
- DODA-poly NIPA-co-MAA-co-VP was prepared by mixing NIPA, MAA, DODA-501 and vinyl pyrrolidone (VP) at a molar ratio of 88 :3 :1 :8 (NIPA:lg, MAA:26.3 ⁇ L, DODA-501 : 0.0646g, VP:92.9 ⁇ L) in 35 mL of anhydrous 1,4-dioxane. The solution was degassed by bubbling N 2 for 15 min and then heated at 69°C overnight. Polymer was recovered by several reprecipitations from diethylether, after solubilization in THF.
- the polymer was dissolved in water and dialysed against water for 48h (MWCO 6000-8000, Spectrum Laboratories, Madison Hills, CA) .
- the suspension was filtered on 0.2 ⁇ m Nylon filter and then freeze-dried for 48h.
- the weight (Mw) and number-average (Mn) molecular weights of the polymer were determined by gel permeation chromatography in THF, using polystyrene standards for calibration.
- the Mw and Mn were 30000 and 14000 respectively, and the polydispersity index was 2.15.
- Copolymer composition was determined by 1 H NMR spectrometry and titration.
- the percentage of MAA was determined by acid-base titration of an ethanol polymer solution (1.6 mg/mL) .
- the MAA content determined by titration was 4.7 mol% MAA.
- the proportion of DODA was measured by NMR analysis, by comparing the integration after deconvolution of the proton signal of NIPA (1.1 ppm) and the proton signal of DODA (0.9 ppm) . It was found that the DODA content of DODAi- poly (NIPA 88 - co-MAA 3 - co-VP 8 ) was 1.4 mol% DODA.
- the proportion of VP was measured, by comparing the integration of the proton signal of NIPA (4.03 ppm) and the proton signal of VP(3.2 ppm) . The VP proportion was found to be 4.9 mol%.
- phase transition pH of the polymer was determined by light scattering (480 nm) at 37°C as described in section A.
- the copolymer DODA-poly (NIPA 8B -co-MAA 3 -c ⁇ -VP B ) starts to precipitate at pH 5.6.
- the critical association concentration (CAC) of the copolymers was determined by a steady-state pyrene fluorescence method described in section A.
- the value of the CAC of the copolymer DODA x -poly was found to be 6 mg/L .
- NIPA co-OD - co-MAA- co-VP Poly (NIPA co-OD - co-MAA- co-VP ) was prepared by mixing NIPA, MAA, octadecylacrylate (ODA) (Aldrich, Milkauwee) and VP at a molar ratio of 87 :3 . - 2 :8 with 1,1'- azobis (cyclohexane carbonitrile) (Aldrich ACCN) used as an initiator (NIPA:lg, MAA:26.6 ⁇ L, ODA:0.0659g, VP:93.9 ⁇ L) in 35 mL of anhydrous 1,4-dioxane. Prior to polymerization, NIPA, MAA, were purified as described in section A.
- the solution was degassed by bubbling N 2 for 15 min and then heated at 69°C overnight.
- Polymer was recovered by several reprecipitations from diethylether, after solubilization in THF. After filtration, the polymer was dissolved in water and dialysed against water for 48h (MWCO 6000-8000, Spectrum Laboratories, Madison Hills, CA) . The suspension was filtered on a 0.2 ⁇ m Nylon filter and then freeze-dried for 48h.
- the weight- (Mw) and number-average (Mn) molecular weight of the polymer was determined by gel permeation chromatography in THF, using polystyrene standards for calibration. Mw and Mn were 26000 and 9000 respectively, and the polydispersity index was 2.8.
- Copolymer composition was determined by X NMR spectrometry and titration
- the percentage of MAA was determined by acid-base titration of an ethanol polymer solution (1.6 mg/mL) .
- the MAA content determined by titration was 4.9 mol% MAA.
- the proportion of ODA was measured using NMR analysis, by comparing the integration after deconvolution of the proton signal of NIPA (1.1 ppm) and the proton signal of ODA (0.9 ppm) . It was found that the ODA content of poly(ODA 2 - co-NIPA 87 - co-MAA 3 - co-VP 8 ) was 2.8 mol% ODA.
- the proportion of VP was measured by comparing the integration of the proton signal of NIPA (4.03 ppm) and the proton signal of VP (3.2 ppm) and found to be 3.6 mol%.
- phase transition pH of the polymer was determined by light scattering (480 nm) at 37°C as described in section A.
- the copolymer poly (ODA 2 -co-NIPA 87 -co-MAA 3 -co-VP 8 ) starts to precipitate at pH 5.4.
- the critical association concentration (CAC) of the copolymers was determined by a steady-state pyrene fluorescence method described in section A.
- the value of the CAC of the copolymer poly (ODA 2 -co-NIPA 87 -co-MAA 3 -co-VP 8 ) was found to be 10 mg/L.
Abstract
Description
Claims
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