Photoactivatable lipid-based nanoparticles as vehicles for dual agent delivery

Patent metadata

Field	Value
Publication number	US-10117942-B2
Application number	US-201414904385-A
Country	US
Kind code	B2
Filing date	Jul 9, 2014
Priority date	Jul 12, 2013
Publication date	Nov 6, 2018
Grant date	Nov 6, 2018

Abstract

Embodiments of photoactivatable, lipid-based nanoparticles are disclosed, as well as methods of making and using the nanoparticles. Pharmaceutical compositions including the nanoparticles also are disclosed. The lipid-based nanoparticles include a vesicle wall surrounding a cavity, wherein the vesicle wall includes (i) a lipid bilayer comprising 1,2-bis(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC8,9PC), dipalmitoylphosphatidylcholine (DPPC), and (ii) 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) within the lipid bilayer. The nanoparticles may further include an agent within the cavity.

First claim

We claim:

1. A photoactivatable lipid-based nanoparticle, comprising:
a vesicle wall surrounding a cavity, the vesicle wall comprising
(i) a lipid bilayer comprising
(a) from 10 mol % to 20 mol % 1,2-bis(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC 8,9 PC),
(b) from 3 mol % to 5 mol % 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol) (DSPE-PEG), and
(c) dipalmitoylphosphatidylcholine (DPPC), and

(ii) 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) within the lipid bilayer,

wherein the vesicle wall has a lipid:HPPH weight ratio from 80:1 to 10:1, and wherein the lipid bilayer is destabilized by targeted application of light having a wavelength of 650-670 nm and a selected intensity for an effective period of time.

2. The photoactivatable lipid-based nanoparticle of claim 1 , wherein the lipid bilayer comprises one or more segregated regions of DC 8,9 PC and the HPPH is preferentially located within the one or more segregated regions of DC 8,9 PC.

3. The photoactivatable lipid-based nanoparticle of claim 1 , wherein the nanoparticle has a diameter from 80 nm to 200 nm.

4. The photoactivatable lipid-based nanoparticle of claim 1 , further comprising at least one agent within the cavity.

5. The photoactivatable lipid-based nanoparticle of claim 4 , wherein the agent is an anti-cancer agent, an imaging agent, or an anti-inflammatory agent.

6. The photoactivatable lipid-based nanoparticle of claim 5 , wherein the agent is an anti-cancer agent.

7. The photoactivatable lipid-based nanoparticle of claim 6 , wherein the agent is topotecan.

8. A pharmaceutical composition comprising a photoactivatable lipid-based nanoparticle according to claim 1 and a pharmaceutically acceptable carrier.

9. The method of claim 1 , wherein the lipid bilayer comprises 76-86 mol % DPPC.

10. A method for delivering an agent from a photoactivatable lipid-based nanoparticle, the method comprising:
providing a photoactivatable lipid-based nanoparticle according to claim 4 ; and
subsequently irradiating the photoactivatable lipid-based nanoparticle with targeted application of light having a wavelength of 650-670 nm and a selected intensity for an effective period of time to activate at least a portion of the HPPH and release at least a portion of the agent from the cavity of the photoactivatable lipid-based nanoparticle.

11. The method of claim 10 , wherein irradiating the photoactivatable lipid-based nanoparticle with targeted application of light comprises irradiating the photoactivatable lipid-based nanoparticle with a laser that produces the light having a wavelength of 650-670 nm.

12. The method of claim 10 , wherein:
(a) the selected intensity is from 1 mW to 500 mW;
(b) the effective period of time is at least 30 seconds; or
(c) both (a) and (b).

13. The method of claim 10 , wherein the agent is a bioactive agent, the method further comprising:
identifying a subject as having a condition that may be treated with HPPH, the bioactive agent, or both HPPH and the bioactive agent;
administering the photoactivatable lipid-based nanoparticle to the subject; and
subsequently irradiating the photoactivatable lipid-based nanoparticle by targeted application of light having a wavelength of 650-670 nm and a selected intensity to a targeted portion of the subject for the effective period of time.

14. The method of claim 13 , wherein the subject has a tumor and the targeted portion of the subject includes an area proximate a location of the tumor.

15. The method of claim 14 , wherein administering the photoactivatable lipid-based nanoparticle to the subject comprises administering an amount of the photoactivatable lipid-based nanoparticle effective to induce tumor size regression.

16. The method of claim 13 , wherein irradiating is performed 4-6 hours after administering the photoactivatable lipid-based nanoparticle to the subject.

17. The method of claim 13 , wherein administering the photoactivatable lipid-based nanoparticle to the subject comprises intravenously injecting the photoactivatable lipid-based nanoparticle into the subject.

18. The method of claim 13 , wherein administering the photoactivatable lipid-based nanoparticle to the subject comprises administering a pharmaceutical composition comprising the photoactivatable lipid-based nanoparticle to the subject.

19. The method of claim 13 , wherein subsequently irradiating the photoactivatable lipid-based nanoparticle by targeted application of light comprises:
externally applying the light to the targeted portion of the subject for the effective period of time, thereby transcutaneously applying the light to the tumor; or
internally applying the light to the targeted portion of the subject for the effective period of time.

20. The method of claim 13 , wherein the bioactive agent is an anti-cancer agent.

21. The method of claim 20 , wherein the anti-cancer agent is topotecan.

Assignees

• Us Health
• Baylor College Medicine

Inventors

• Puri Anu
• Blumenthal Robert P
• Joshi Amit
• Tata Darayash B
• Viard Mathias

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K41/0071 Primary

  PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines · CPC title

• A61K9/1271

  Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911}) · CPC title

• A61K31/704

  attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)} · CPC title

• A61K41/0042

  Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion · CPC title