BRANCHED POLYESTER CARRYING DENDRONS

Abstract

Branched polyesters carrying dendrons are a useful class of nanomaterials which exhibit good handling properties and stability, can degrade to a high extent, and are effective encapsulation materials. They can be used to make nanoprecipitated particles which may for example be used in therapy. Furthermore, these materials can be synthesised by economical and tailorable processes. The materials can be prepared by the ring-opening polymerisation (ROP) of mono-functional lactone monomers and difunctional lactone monomers, using dendron initiators.

Claims

1. A product which is a branched polyester carrying dendrons.

2. A product as claimed in claim 1 comprising polyester chains linked by branches, wherein the polyester chains have between 1 and 6 carbon atoms between ester linkages.

3. A product as claimed in claim 2 wherein the polyester chains have 5 carbon atoms between ester linkages.

4. A product as claimed in claim 2 wherein the polyester chains have 1 carbon atom between ester linkages.

5. A product as claimed in any preceding claim wherein each branch is a single covalent bond.

6. A product as claimed in any of claims 1 to 4 wherein each branch comprises between 1 and 6 carbon atoms.

7. A product as claimed in any preceding claim which is non-gelled.

8. A product as claimed in any preceding claim having on average one branch or fewer per polyester chain.

9. A product as claimed in any preceding claim wherein the dendrons are present at the ends of polyester chains.

10. A product which is a branched polymer scaffold carrying moieties, wherein the branched polymer scaffold comprises polyester, and wherein the moieties comprise a dendron.

11. A product as claimed in claim 10, having feature(s) as defined in any of claims 2 to 9.

12. A product as claimed in claim 10 or claim 11 wherein the branched polymer scaffold comprises not only polyester but also other polymer.

13. A product as claimed in any of claims 10 to 12 wherein the moieties comprise not only a dendron but also one or more further moiety.

14. A product as claimed in claim 13 wherein a further moiety is a further dendron.

15. A product as claimed in claim 13 or claim 14 wherein a further moiety is not a dendron.

16. A product as claimed in claim 15 wherein the moiety which is not a dendron comprises a PEG group.

17. A method of preparing a branched polyester carrying dendrons, comprising ring-opening polymerisation (ROP) of a monofunctional lactone monomer and a difunctional lactone monomer, using a dendron initiator.

18. A method as claimed in claim 17 wherein the monofunctional lactone monomer is caprolactone, or a mixture of caprolactone and another monofunctional lactone monomer.

19. A method as claimed in claim 17 wherein the monofunctional lactone monomer is lactide, glycolide, or a mixture of lactide and glycolide.

20. A method as claimed in any of claims 17 to 19 wherein the difunctional lactone monomer is BOD (4,4-bioxepanyl-7-7-dione).

21. A method as claimed in any of claims 17 to 20 wherein the ROP is metal-catalysed.

22. A method as claimed in any of claims 17 to 20 wherein the ROP is acid-catalysed cationic ROP.

23. A method of preparing a branched polymer scaffold carrying dendrons and optionally other moieties, comprising ring-opening polymerisation (ROP) of lactone using a dendron initiator.

24. A method as claimed in claim 23, having feature(s) as defined in any of claims 17 to 22.

25. A method as claimed in claim 23 or claim 24 comprising not only ROP but also other polymerisation.

26. A method as claimed in any of claims 23 to 25 using not only one dendron initiator but also one or more further initiator.

27. A method as claimed in claim 26 wherein a further initiator is a further dendron initiator.

28. A method as claimed in claim 26 or claim 27 wherein a further initiator is not a dendron initiator.

29. A method as claimed in claim 28 wherein the initiator which is not a dendron initiator comprises a PEG group.

30. A product obtainable by the method of any of claims 17 to 29.

31. Use of a product as claimed in any of claim 1 to 16 or 30 in encapsulation.

32. A pharmaceutical composition comprising a product as claimed in any of claim 1 to 16 or 30.

33. A product as claimed in any of claim 1 to 16 or 30, loaded with a therapeutically active material, for use in therapy.

34. A method of medical treatment comprising administration of a product as claimed in any of claim 1 to 16 or 30, loaded with a therapeutically active material, to a subject.

Description

[0036] The present invention will now be described, by way of example only, in further non-limiting detail, with reference to the following figures and examples in which:

[0037] FIG. 1 shows a reaction scheme according to which a dendron initiator may be reacted with a difunctional lactone monomer and a monofunctional lactone monomer to form a polydendron material which comprises a non-crosslinked polyester core carrying a plurality of dendrons;

[0038] FIG. 2 shows a size-exclusion chromatogram (SEC) demonstrating the reliable degradation of products in accordance with the present invention to low molecular weight materials; and

[0039] FIG. 3 shows polydendron materials wherein the polymer scaffold carries not only dendrons but also other moieties.

EXAMPLES

[0040] A. Ring Opening Polymerisation of -caprolactone using Tertiary Amine Functionalised Dendritic Initiators

[0041] 1.0 Initiator Synthesis

[0042] 1.1 Generation 1 (G.sub.1) dendron ROP initiator synthesis

##STR00002##

[0043] [G.sub.1 dendron ROP initiator]; [2]-2-(Dimethylamino)ethyl acrylate (DMEA) (6.0 g, 42 mmol, 6 eq.) was added to a 50 mL round 2 necked round-bottomed flask containing propan-2-ol (IPA) (12 mL). The flask was deoxygenated under a positive N.sub.2 purge for 10 minutes. Ethanolamine [1] (0.4266 g, 7.0 mmol, 1 eq.) dissolved in IPA (12 mL) was added drop wise while the solution was stirring in an ice bath under a positive flow of N.sub.2. The final mixture was stirred for a further 10 minutes at 0 C. before being allowed to warm to room temperature and left stirring for 48 hr. The solvent was removed and the product left to dry in vacuo overnight. Yield: 2.33 g, yellow oil (96%). .sup.1H NMR (400 MHz, CDCl.sub.3) 2.27 (s, 12H), 2.44-2.61 (m, 10H), 2.81 (t, 4H), 3.57 (t, 2H), 4.18 (t, 4H). .sup.13C NMR (100 MHz, CDCl3) 32.6, 45.6, 49.4, 56.2, 57.8, 59.5, 62.0, 172.7. Calcd [M+H].sup.+ (C.sub.16H.sub.33N.sub.3O.sub.5) m/z=347.5. Found: ESI-MS: [M+H].sup.+ m/z=348.2. Anal. Calcd for C.sub.16H.sub.33N.sub.3O.sub.5: C, 55.26; H, 9.50; N, 12.09%. Found C, 57.09; H, 9.47; N, 11.02%.

[0044] [2] was prepared using the literature procedure: Polymer Chemistry, 2015, 6, 573

[0045] 1.2 Synthesis of 1-[N, N-bis (2-aminopropyl)-amino]-1-propanol (APAP)

##STR00003##

[0046] 1.2.1 Synthesis of [.sup.tBOC.sub.2-BAPA-G1]

##STR00004##

[0047] [.sup.tBOC.sub.2-BAPA-G.sub.1]; [5]Carbonyl diimidazole (CDI) (19.55 g, 0.121 mol, 2 eq.) was added to an oven-dried 500 mL 2-neck RBF fitted with a reflux condenser, magnetic stirrer and a dry N.sub.2 inlet. 350 mL of anhydrous toluene was added and the flask purged with N.sub.2 for 10 minutes. The solution was stirred at 60 C. and tertiary butanol

[0048] [3] (17.83 g, 23 mL, 0.241 mol, 4 eq.) was added via a warm syringe. The mixture was left stirring at 60 C. for 6 hr under a positive flow of nitrogen. Bis(3-aminopropyl)amine (7.88 g, 8.4 mL, 0.060 mol, 1 eq.) was added dropwise, and the reaction was left stirring for a further 18 hr at 60 C. under a positive flow of nitrogen. Following this, the solution was allowed to cool to room temperature, and the pale yellow solution was filtered to remove any solid imidazole, and concentrated in vacuo. The resulting viscous oil was dissolved in dichloromethane (200 mL) washed with distilled water (3200 mL) and once with brine (150 mL). The organic layer was dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. Yield: 16.63 g, white solid, (84%). .sup.1H NMR (400 MHz, CDCl.sub.3): =1.43 (s, 18H), 1.63 (m, 4H), 2.64 (t, 4H), 3.20 (t, 4H), 5.19 (s, br, NH). .sup.13C NMR (100 MHz, CDCl.sub.3): =28.5, 29.9, 39.0, 47.7, 79.2, 156.2. Calcd: [M+H].sup.+ (C.sub.16H.sub.33N.sub.3O.sub.4) m/z=332.3. Found: ESI-MS: [M+H].sup.+ m/z=332.3. Anal. Calcd for C.sub.16H.sub.33N.sub.3O.sub.4: C, 58.00; H, 10.00; N, 12.69. Found: C, 57.78; H, 9.92; N, 12.82.

[0049] [5] was prepared using the literature procedure: Soft Matter, 2012, 8, 1096.

[0050] 1.2.2 Synthesis of [.sup.tBOC.sub.2-APAP-pOH]

##STR00005##

[0051] [.sup.tBOC.sub.2-APAP-pOH]; [6]-[5] (15.38 g, 0.046 mol, 1 eq.), bromoethanol (5.81 g, 3.3 L, 0.046 mol, 1 eq.), sodium iodide (150 mg), potassium carbonate (19.27 g, 0.139 mol, 3 eq.) and 1,4-dioxane (150 mL) was added to a 500 mL 2-necked RBF fitted with a reflux condenser and magnetic stirrer. The reaction was refluxed overnight. After this time, water (150 mL) was added to the reaction mixture and the product was extracted with ethyl acetate (2225 mL). The combined extracts were washed with water (1150 mL), dried over sodium sulfate and concentrated in vacuo. The crude product purified by liquid chromatography (silica gel, eluting with EtOAc:MeOH, 80:20). Yield: 7.55 g, pale yellow oil at ambient temperature, solidifying to an off white solid upon cooling, (43%). .sup.1H NMR (400 MHz, CDCl.sub.3): =1.41 (s, 18H), 1.62 (m, 4H), 2.47 (t, 4H), 2.54 (t, 2H), 2.85 (s, br, OH), 3.16 (m, 4H), 3.57 (t, 2H), 5.09 (s, br, NH). .sup.13C NMR (100 MHz, CDCl.sub.3): =27.2, 28.4, 38.9, 51.7, 56.0, 58.9, 79.1, 156.2. Calcd: [M+H].sup.+ (C.sub.18H.sub.37N.sub.3O.sub.5) m/z=376.5. Found: ESI-MS: [M+H].sup.+ m/z=376.3. Anal. Calcd for C.sub.18H.sub.37N.sub.3O.sub.5: C, 57.52; H, 9.85; N, 11.18. Found: C, 56.97; H, 9.81; N, 11.02.

[0052] [6] was prepared using the literature procedure: Journal of Medicinal Chemistry, 1994, 37 (15), 2334.

[0053] 1.2.3 Synthesis of 1-[N, N-bis (2-aminopropyl)-amino]-1-propanol (APAP)

##STR00006##

[0054] [APAP]; [8]To a 500 mL RBF, 6 (7.49 g, 0.02 mol, 1 eq.) was dissolved in ethyl acetate (80 mL), and had concentrated HCl (12.14 g, 10.3 mL, 36% active) added very slowly. CO.sub.2 began to rapidly evolve. The reaction vessel was left open to the atmosphere, heated to 50 C. and stirred for 24 hr. After removal of ethyl acetate in vacuo, the crude oil was dissolved very slowly in 4M NaOH (80 mL), and reduced by approximately half its volume on the rotary evaporator (60 C.). A yellow oily substance formed on the surface of the NaOH solution. The mixture was extracted with CHCl.sub.3 (280 mL), the organic layers combined, dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. Yield: 2.98 g, pale yellow oil (85%). .sup.1H NMR (400 MHz, CDCl.sub.3): =1.54 (m, 4H), 2.48 (m, 6H), 2.70 (t, 4H), 3.53 (t, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3): =30.58, 40.37, 52.01, 56.02, 59.77. Calcd: [M+H].sup.+ (C.sub.8H.sub.21N.sub.3O) m/z=175.05. Found: CI-MS: [M+H].sup.+ m/z=176.2. Anal. Calcd for C.sub.8H.sub.21 N.sub.3O: C, 54.86; H, 12.00; N, 24.00%. Found: C, 53.47; H, 12.06; N, 23.67%.

[0055] [8] was prepared using the literature procedure: Soft Matter, 2012, 8, 1096.

[0056] 1.3 Generation 2 (G.sub.2) dendron ROP initiator synthesis

##STR00007##

[0057] [G.sub.2 dendron ROP initiator]; [9]DMEA (6.0 g, 0.042 mol, 6 eq.) was added to a 50 mL round 2 necked round-bottomed flask containing IPA (12 mL). The flask was deoxygenated under a positive N.sub.2 purge for 10 minutes. [8] (1.2222 g, 0.007 mmol, 1 eq.) dissolved in IPA (12 mL) was added drop wise while the solution was stirring in an ice bath under a positive flow of N.sub.2. The final mixture was stirred for a further 10 minutes at 0 C., allowed to warm to room temperature and left stirring for 48 hr. The solvent was removed and the product left to dry in vacuo overnight. Yield: 4.84 g, yellow oil, (93%). .sup.1H NMR (400 MHz, CDCl.sub.3) 1.52 (m, 4H), 2.23 (s, 24H), 2.41 (m, 16H). 2.51 (t, 10H), 2.72 (t, 8H), 3.50 (t, 2H), 4.11 (t, 8H). .sup.13C NMR (100 MHz, CDCl3) 24.62, 32.24, 45.68, 48.94, 51.53, 51.89, 55.76, 57.82, 59.48, 62.15, 172.6. Calcd [M+H].sup.+ (C.sub.36H.sub.73O.sub.9N.sub.7) m/z=748.01. Found: ESI-MS: [M+H].sup.+ m/z=748.6. Anal. Calcd for C.sub.36H.sub.73O.sub.9N.sub.7: C, 57.75; H, 9.76; N, 13.10%. Found: C, 57.50; H, 9.76; N, 13.01%.

[0058] [9] was prepared using the literature procedure: Polymer Chemistry, 2015, 6, 573

[0059] 2.0 4,4-bioxepanyl-7,7-dione (BOD) synthesis

##STR00008##

[0060] [BOD]; [12]Urea hydrogen peroxide (10 g, 0.106 mol, 25 eq.) was added to a 250 mL RBF containing formic acid [10] (100 mL, 2.65 mol, 1 eq.). The solution was stirred for 2 hr at room temperature. The flask was then immersed in an ice bath and had bicyclohexanone (10 g, 0.026 mol, 100 eq.) was slowly added to the solution. The reaction mixture was stirred for 4 hr. Water (100 mL) was then added to the mixture and the product was extracted with chloroform (3100 mL). The organic fractions were collected and washed with saturated aqueous sodium bicarbonate solution (100 mL) then dried over night with Na.sub.2SO.sub.4. After removing the solvent, a white powder was isolated and dried under vacuum overnight. Yield: 3.26 g, white solid, (56%). .sup.1H NMR (400 MHz, CDCl.sub.3) 1.50 (m, 2H), 1.66 (m, 4H), 1.87 (m, 4H), 2.51-2.82 (d of t, 4H), 4.08-4.44 (d of t, 4H). .sup.13C NMR (100 MHz, CDCl3) 29.6, 35.9, 37.1, 49.7, 72.4, 181.3. Calcd [M+H].sup.+ (C.sub.12H.sub.18O.sub.4) m/z=226.3. Found: ESI-MS: [M+H].sup.+ m/z=228.2. Anal. Calcd for C.sub.12H.sub.18O.sub.4: C, 63.64; H, 7.96%. Found: C, 61.67; H, 7.72%.

[0061] [12] was prepared using the literature procedure: Polymer Chemistry, 5 (8), 2997-3008

[0062] 3.0 Ring Opening Polymerisation of -caprolactone

[0063] 3.1 Typical Polymerisation of -caprolactone (CL)

[0064] [General procedure for Bn- and G.sub.0-p(CL.sub.x)]; In a typical experiment, Sn(oct).sub.2 (0.006 g, 0.0014 mmol, 1/350 eq.) was added using a dry syringe to a RBF equipped with a magnetic stirrer bar flushed with dry nitrogen. Following this, CL (17.75 g, 16.5 mL, 0.16 mol, 30 eq.) was added using a dry syringe. The reaction mixture was degassed for a further 15 minutes and then immersed in a silicon oil bath at 110 C. 2-dimethylaminoethanol (G.sub.0 dendron ROP initiator) (0.4621 g, 0.52 mL, 0.005 mol, 1 eq.) was added via a dry syringe and the polymerisation left for 20 hr. The polymerisation was stopped by removing the reaction mixture from the heat and immersing it in an ice bath. The crude product was dissolved in 50 mL of tetrahydrofuran (THF) and precipitated from 600 mL of hexane. The precipitated polymer was dried under vacuum for 24 hr.

[0065] [General procedure for G.sub.1- and G.sub.2-p(CL.sub.x)]; In a typical experiment, Sn(oct).sub.2 (0.0055 g, 0.014 mmol, 1/150 eq.) and G.sub.1 dendron ROP initiator [2] (0.7066 g, 0.002 mol, 1 eq.) were added to a RBF equipped with a magnetic stirrer bar flushed with dry nitrogen. The reaction mixture was degassed for a further 15 minutes and then immersed in a silicon oil bath at 110 C. Following this, CL (6.97 g, 6.5 mL, 0.06 mol, 30 eq.) was added using a dry syringe and the polymerisation left for 48 hr. The polymerisation was stopped by removing the reaction mixture from the heat and immersing it in an ice bath. The crude product was dissolved in 50 mL of THF and precipitated from 600 mL of hexane. The precipitated polymer was dried under vacuum for 24 hr.

[0066] Polymers were prepared using literature procedures: Macromolecules 1997, 30, 8508, Chem. Comm., 2006, 4010 and Macromolecules, 1998, 31, 2756.

TABLE-US-00001 TABLE 1 SEC analysis of linear benzyl-functional polymer and amine-functional linear-dendritic hybrids [I]/ Theoretical Mn (Da) Mw (Da) Polymer [catalyst Mn (Da) (GPC).sup.a (GPC).sup.a Mw/Mn Bn-p(CL.sub.30) 350 3,420 5,420 7,480 1.38 G.sub.0-p(CL.sub.20) 350 2,280 1,790 2,520 1.41 G.sub.0-p(CL.sub.30) 350 3,420 2,780 3,950 1.42 G.sub.0-p(CL.sub.50) 350 5,710 4,820 6,665 1.38 G.sub.1-p(CL.sub.20) 200 2,280 2,220 3,754 1.70 G.sub.1-p(CL.sub.30) 350 3,420 3,090 6,050 1.96 G.sub.1-p(CL.sub.50) 150 5,710 6,650 9,640 1.45 G.sub.2-p(CL.sub.30) 350 3,420 5,210 11,460 2.20 .sup.aTriple detection analysis using THF/2% TEA as eluent

[0067] 3.2 Typical polymerisation of CL and 4,4-bioxepanyl-7,7-dione (BOD)

[0068] [General procedure for Bn- and G.sub.0-p(CL.sub.30-co-BOD.sub.x)]; In a typical experiment, Sn(oct).sub.2(0.002 g, 0.005 mmol, 1/350 eq.) and BOD (0.3128 g, 0.0014 mol, 0.8 eq.) were added to a RBF equipped with a magnetic stirrer bar flushed with dry nitrogen. Following this, CL (5.9 g, 5.5 mL, 0.052 mol, 30 eq.) was added using a dry syringe. The reaction mixture was degassed for a further 15 minutes and then immersed in a silicon oil bath at 110 C. G.sub.0 dendron ROP initiator (0.15 g, 0.17 mL, 0.0017 mol, 1 eq.) was added via a dry syringe and the polymerisation left for 20 hr. The polymerisation was stopped by removing the reaction mixture from the heat and immersing it in an ice bath. The crude product was dissolved in 50 mL of THF and precipitated from 600 mL of hexane. The precipitated polymer was dried under vacuum for 24 hr.

[0069] [General procedure for G.sub.1- and G.sub.2-p(CL.sub.30-co-BOD.sub.x)]; In a typical experiment, Sn(oct).sub.2(0.0032 g, 0.007 mmol, 1/200 eq.), BOD (0.2849 g, 0.0013 mol, 0.8 eq.) and [2] (0.5469 g, 0.0016 mol, 1 eq.) were added to a RBF equipped with a magnetic stirrer bar flushed with dry nitrogen. The reaction mixture was degassed for a further 15 minutes and then immersed in a silicon oil bath at 110 C. Following this, CL (5.4 g, 5 mL, 0.047 mol, 30 eq.) was added using a dry syringe and the polymerisation left for 14 hr. The polymerisation was stopped by removing the reaction mixture from the heat and immersing it in an ice bath. The crude product was dissolved in 30 mL of THF and precipitated from 600 mL of hexane. The precipitated polymer was dried under vacuum for 24 hr.

TABLE-US-00002 TABLE 2 SEC analysis of hyperbranched benzyl-functional polymer and hyperbranched amine-functional polydendrons Mn (Da) Mw (Da) Polymer (GPC).sup.a (GPC).sup.a Mw/Mn Bn-p(CL.sub.30-co-BOD.sub.1.0) 5,600 108,560 19.39 G.sub.0-p(CL.sub.30-co-BOD.sub.1.0) 9,480 129,510 13.67 G.sub.1-p(CL.sub.30-co-BOD.sub.0.8) 3,250 92,580 28.50 G.sub.2-p(CL.sub.30-co-BOD.sub.1.0) .sup.aTriple detection analysis using THF/2% TEA as eluent

[0070] 4.0 Degradation Studies

[0071] Polymers for degradation experiments were prepared in a phosphate buffered saline (PBS) solution (0.02 mol L.sup.1, pH=7.4). Each polymer (1 g) was placed into a capped vial containing 20 mL PBS (0.02 mol L.sup.1, pH=7.4). The vial was then left standing at room temperature. At predetermined time intervals, samples were withdrawn (1 mL), frozen in liquid nitrogen and lyophilised for 24 hours. They were then dissolved in a THF/2 v/v% TEA eluent system and analysed by GPC. Degradation studies were carried out following the literature procedure: Polymer Chem. 2014, 5 (13), 4002

[0072] FIG. 2 shows an SEC chromatogram of: [0073] Bn-p{CL.sub.30) (dotted trace) [0074] Bn-p(CL.sub.30) 4 weeks in PBS (solid bold trace) [0075] Bn-p(CL.sub.30) 6 weeks in PBS (solid faint trace) and [0076] Bn-p(CL.sub.30) 8 weeks in PBS (dashed trace)

[0077] 5.0 Nanoparticle Formation

[0078] [General procedure for aqueous nanoprecipitation of p(CL.sub.30) and p(CL.sub.30-co-BOD.sub.x)]-The materials were dissolved in THF at a concentration of 5 mg mL.sup.1. 2 mL of this solution was then subjected to a rapid solvent switch through drop wise addition into 10 mL of water, to give a final polymer concentration of 1 mg mL.sup.1 in water after THF removal by evaporation overnight.

TABLE-US-00003 TABLE 3 DLS analysis of nanoprecipitated particles from linear-dendritic polymer hybrids Nanoprecipitated into water pH = 4 Polymer D.sub.z(nm).sup.a PDI (mV).sup.b Bn-p(CL.sub.30) G.sub.0-p(CL.sub.30) 123 0.140 +84 G.sub.0-p(CL.sub.50) 97 0.184 +51 G.sub.1-p(CL.sub.30) 130 0.259 +66 G.sub.1-p(CL.sub.50) 122, 0.148 +62 G.sub.2-p(CL.sub.30) .sup.aAll diameters are given as z-average values as measured by dynamic light scattering. .sup.bAll zeta potentials are given as surface charge values as measured by dynamic light scattering.

TABLE-US-00004 TABLE 4 DLS analysis of nanoprecipitated particles from hyperbranched polydendrons pH of water pH = 4 pH = 7.8 Polymer D.sub.z (nm).sup.a PDI (mV).sup.b D.sub.z (nm).sup.a PDI (mV).sup.b Bn-p (CL.sub.30-co- BOD.sub.1.0) G.sub.0-p (CL.sub.30-co- 145 0.140 +53 BOD.sub.1.0) G.sub.1-p (CL.sub.30- 137 0.185 +48 151 0.081 +30 co-BOD.sub.0.8) G.sub.2-p (CL.sub.30-co- BOD.sub.1.0), .sup.aAll diameters are given as z-average values as measured by dynamic light scattering. .sup.bAll zeta potentials are given as surface charge values as measured by dynamic light scattering.

[0079] 6.0 Stability Testing

[0080] [General procedure for stability testing of p(CL.sub.30-co-BOD.sub.x)]-NaOH (0.14 M) (1 mL) was added to the NP dispersion (1 mg mL.sup.1) (10 mL) prepared in water at pH=7.8.

TABLE-US-00005 TABLE 5 DLS analysis of nanoprecipitated particles from hyperbranched polydendrons before and after salt addition pH = 7.8 + salt.sup.a Polymer D.sub.z (nm).sup.b PDI (mV).sup.c D.sub.z (nm).sup.b PDI (mV).sup.c Bn-p (CL.sub.30-co- BOD.sub.1.0) G.sub.0-p (CL.sub.30-co- BOD.sub.1.0) G.sub.1-p (CL.sub.30-co- 147 0.077 +35 148 0.078 +35 BOD.sub.0.8) G.sub.2-p (CL.sub.30-co- BOD.sub.1.0), .sup.aAddition of NaOH (0.14M) (1 mL) to NP dispersion (1 mg mL.sup.1) (10 mL) .sup.bAll diameters are given as z-average values as measured by dynamic light scattering. .sup.cAll zeta potentials are given as surface charge values as measured by dynamic light scattering.

[0081] 7.0 Fluoresceinamine Encapsulation

[0082] [General procedure for fluoresceinamine encapsulation of p(CL.sub.30-co-BOD.)]Fluoresceinamine was dissolved in THF at a concentration of 1 mg mL.sup.1. 1 mL of this solution, along with 2 mL of the polymer solution (5 mg mL.sup.1), was then subjected to a rapid solvent switch through drop wise addition into 10 mL of water, to give a final polymer concentration of 1 mg mL.sup.1, and fluoresceinamine concentration of 0.1 mg mL.sup.1 (10 wt % loading) in water after THF removal by evaporation overnight.

TABLE-US-00006 TABLE 6 DLS analysis of fluoresceinamine encapsulated nanoprecipitated particles from hyperbranched polydendrons Polymer D.sub.z(nm).sup.a PDI Bn-p(CL.sub.30-co-BOD.sub.1.0) G.sub.0-p(CL.sub.30-co-BOD.sub.1.0) G.sub.1-p(CL.sub.30-co-BOD.sub.0.8) 85 0.167 G.sub.2-p(CL.sub.30-co-BOD.sub.1.0), .sup.aAll diameters are given as z-average values as measured by dynamic light scattering.

[0083] B. Ring Opening Polymerisations using Lactide and other Components

[0084] Analogous polymerisations using lactide, in place of and in addition to caprolactone, were also carried out, with OH-containing initiators and acid catalysis. ROP of lactide yielded polylactide linear polymers. ROP of lactide with caprolactone yielded polycaprolactone-polylactide copolymers. ROP of lactide with BOD yielded branched polylactides. Similarly to branched polymer cores based on caprolactone, branched polymers based on lactide are also effective; they can form soluble, high molecular weight materials, and can be nanoprecipitated to form nanoparticles.