D-peptide hydrogels as a long-acting multipurpose drug delivery platform for combined contraception and HIV prevention

Sreekanth Pentlavalli; Sophie Coulter; Yuming  An; Emily R Cross; Han Sun; Jessica V Moore; Akmal Hidayat Bin Sabri; B Greer; Lalitkumar K. Vora; Helen O. McCarthy; Garry Laverty

doi:10.1016/j.jconrel.2024.12.052

D-peptide hydrogels as a long-acting multipurpose drug delivery platform for combined contraception and HIV prevention

Sreekanth Pentlavalli
, Sophie Coulter
, Yuming An
, Emily R Cross
, Han Sun
, Jessica V Moore
, Akmal Hidayat Bin Sabri
, B Greer
, Lalitkumar K. Vora
, Helen O. McCarthy
, Garry Laverty

Queens University Belfast

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

54 Downloads (Pure)

Abstract

New multipurpose prevention technology products for use by women, focused on reducing HIV infection and
preventing unwanted pregnancies, are a global health priority. Discreet long-acting formulations will empower
women with greater choice around their sexual health. This paper outlines the development of a long-acting
technology that enables multiple drugs to be incorporated within one injectable platform. This fixed-dose
combination product is formed from a phosphorylated D-peptide (naphthalene-2-ly)-acetyl-diphenylalaninelysine-tyrosine-glycine-OH (Napffky(p)G-OH) that enables the highly hydrophobic drugs MIV-150 (HIV antiretroviral) and etonogestrel (contraceptive) to be solubilized together within aqueous solvents. Upon subcutaneous
injection, this D-peptide-drug combination self-assembles in response to phosphatase enzymes present within the
skin space to form an in situ forming drug-releasing hydrogel depot. Oscillatory rheology confirmed the formation
of hydrogels, which began within ~10 s exposure to 3.98 U/mL phosphatase enzymes and continued for ~198
mins for a Napffk(MIV-150)y(p)G-OH + Napffk(ENG)y(p)G-OH combination (8:2 ratio). Biostability against
proteases, an important consideration for long-acting injectables, was demonstrated for at least 28 days in vitro.
Covalent attachment of each drug to the D-peptide via an ester linkage enabled sustained release of the drug in an
unmodified form via hydrolysis of the D-peptide-drug linker. This significantly reduced the initial drug burst.
Low toxicity was also demonstrated in vitro via cell culture (MTS, LHS, Live/Dead®) and within in vivo studies
(H&E staining). The fixed dose combination was able to deliver clinically relevant concentrations of each drug to
Sprague–Dawley rats for at least 49 days, providing proof-of-concept for the use of hydrogel-forming D-peptides
(Napffky(p)G-OH) as a long-acting injectable platform for the delivery of multiple hydrophobic drugs.

Original language	English
Pages (from-to)	30-44
Number of pages	15
Journal	Journal of Controlled Release
Volume	379
Early online date	8 Jan 2025
DOIs	https://doi.org/10.1016/j.jconrel.2024.12.052
Publication status	Published (in print/issue) - 10 Mar 2025

Bibliographical note

Data Availability Statement

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

Funding

This work was supported by the EPSRC [grant number EP/S031561/1]; the Wellcome Trust [grant number 07618/Z/17/Z]; the MRC [grant number MC_PC_18060] and Invest NI [grant number 2111/130282815] awards to GL.

Funders	Funder number
Engineering and Physical Sciences Research Council	EP/S031561/1
Engineering and Physical Sciences Research Council
Wellcome Trust	07618/Z/17/Z
Wellcome Trust
Medical Research Council	MC_PC_18060
Medical Research Council
Invest Northern Ireland	2111/130282815
Invest Northern Ireland

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Long-acting injectable
Peptide hydrogel
Sustained release
HIV/AIDS
Contraception
Enzyme instructed self-assembly
Multipurpose prevention technologies

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Cite this

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title = "D-peptide hydrogels as a long-acting multipurpose drug delivery platform for combined contraception and HIV prevention",

abstract = "New multipurpose prevention technology products for use by women, focused on reducing HIV infection and preventing unwanted pregnancies, are a global health priority. Discreet long-acting formulations will empower women with greater choice around their sexual health. This paper outlines the development of a long-acting technology that enables multiple drugs to be incorporated within one injectable platform. This fixed-dose combination product is formed from a phosphorylated D-peptide (naphthalene-2-ly)-acetyl-diphenylalaninelysine-tyrosine-glycine-OH (Napffky(p)G-OH) that enables the highly hydrophobic drugs MIV-150 (HIV antiretroviral) and etonogestrel (contraceptive) to be solubilized together within aqueous solvents. Upon subcutaneous injection, this D-peptide-drug combination self-assembles in response to phosphatase enzymes present within the skin space to form an in situ forming drug-releasing hydrogel depot. Oscillatory rheology confirmed the formation of hydrogels, which began within \textasciitilde{}10 s exposure to 3.98 U/mL phosphatase enzymes and continued for \textasciitilde{}198 mins for a Napffk(MIV-150)y(p)G-OH + Napffk(ENG)y(p)G-OH combination (8:2 ratio). Biostability against proteases, an important consideration for long-acting injectables, was demonstrated for at least 28 days in vitro. Covalent attachment of each drug to the D-peptide via an ester linkage enabled sustained release of the drug in an unmodified form via hydrolysis of the D-peptide-drug linker. This significantly reduced the initial drug burst. Low toxicity was also demonstrated in vitro via cell culture (MTS, LHS, Live/Dead{\textregistered}) and within in vivo studies (H\&E staining). The fixed dose combination was able to deliver clinically relevant concentrations of each drug to Sprague–Dawley rats for at least 49 days, providing proof-of-concept for the use of hydrogel-forming D-peptides (Napffky(p)G-OH) as a long-acting injectable platform for the delivery of multiple hydrophobic drugs.",

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author = "Sreekanth Pentlavalli and Sophie Coulter and Yuming An and Cross, \{Emily R\} and Han Sun and Moore, \{Jessica V\} and Sabri, \{Akmal Hidayat Bin\} and B Greer and Vora, \{Lalitkumar K.\} and McCarthy, \{Helen O.\} and Garry Laverty",

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AU - Pentlavalli, Sreekanth

AU - Coulter, Sophie

AU - An, Yuming

AU - Cross, Emily R

AU - Sun, Han

AU - Moore, Jessica V

AU - Sabri, Akmal Hidayat Bin

AU - Greer, B

AU - Vora, Lalitkumar K.

AU - McCarthy, Helen O.

AU - Laverty , Garry

PY - 2025/3/10

Y1 - 2025/3/10

N2 - New multipurpose prevention technology products for use by women, focused on reducing HIV infection and preventing unwanted pregnancies, are a global health priority. Discreet long-acting formulations will empower women with greater choice around their sexual health. This paper outlines the development of a long-acting technology that enables multiple drugs to be incorporated within one injectable platform. This fixed-dose combination product is formed from a phosphorylated D-peptide (naphthalene-2-ly)-acetyl-diphenylalaninelysine-tyrosine-glycine-OH (Napffky(p)G-OH) that enables the highly hydrophobic drugs MIV-150 (HIV antiretroviral) and etonogestrel (contraceptive) to be solubilized together within aqueous solvents. Upon subcutaneous injection, this D-peptide-drug combination self-assembles in response to phosphatase enzymes present within the skin space to form an in situ forming drug-releasing hydrogel depot. Oscillatory rheology confirmed the formation of hydrogels, which began within ~10 s exposure to 3.98 U/mL phosphatase enzymes and continued for ~198 mins for a Napffk(MIV-150)y(p)G-OH + Napffk(ENG)y(p)G-OH combination (8:2 ratio). Biostability against proteases, an important consideration for long-acting injectables, was demonstrated for at least 28 days in vitro. Covalent attachment of each drug to the D-peptide via an ester linkage enabled sustained release of the drug in an unmodified form via hydrolysis of the D-peptide-drug linker. This significantly reduced the initial drug burst. Low toxicity was also demonstrated in vitro via cell culture (MTS, LHS, Live/Dead®) and within in vivo studies (H&E staining). The fixed dose combination was able to deliver clinically relevant concentrations of each drug to Sprague–Dawley rats for at least 49 days, providing proof-of-concept for the use of hydrogel-forming D-peptides (Napffky(p)G-OH) as a long-acting injectable platform for the delivery of multiple hydrophobic drugs.

AB - New multipurpose prevention technology products for use by women, focused on reducing HIV infection and preventing unwanted pregnancies, are a global health priority. Discreet long-acting formulations will empower women with greater choice around their sexual health. This paper outlines the development of a long-acting technology that enables multiple drugs to be incorporated within one injectable platform. This fixed-dose combination product is formed from a phosphorylated D-peptide (naphthalene-2-ly)-acetyl-diphenylalaninelysine-tyrosine-glycine-OH (Napffky(p)G-OH) that enables the highly hydrophobic drugs MIV-150 (HIV antiretroviral) and etonogestrel (contraceptive) to be solubilized together within aqueous solvents. Upon subcutaneous injection, this D-peptide-drug combination self-assembles in response to phosphatase enzymes present within the skin space to form an in situ forming drug-releasing hydrogel depot. Oscillatory rheology confirmed the formation of hydrogels, which began within ~10 s exposure to 3.98 U/mL phosphatase enzymes and continued for ~198 mins for a Napffk(MIV-150)y(p)G-OH + Napffk(ENG)y(p)G-OH combination (8:2 ratio). Biostability against proteases, an important consideration for long-acting injectables, was demonstrated for at least 28 days in vitro. Covalent attachment of each drug to the D-peptide via an ester linkage enabled sustained release of the drug in an unmodified form via hydrolysis of the D-peptide-drug linker. This significantly reduced the initial drug burst. Low toxicity was also demonstrated in vitro via cell culture (MTS, LHS, Live/Dead®) and within in vivo studies (H&E staining). The fixed dose combination was able to deliver clinically relevant concentrations of each drug to Sprague–Dawley rats for at least 49 days, providing proof-of-concept for the use of hydrogel-forming D-peptides (Napffky(p)G-OH) as a long-acting injectable platform for the delivery of multiple hydrophobic drugs.

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ER -

D-peptide hydrogels as a long-acting multipurpose drug delivery platform for combined contraception and HIV prevention

Abstract

Bibliographical note

Data Availability Statement

Funding

UN SDGs

Keywords

Access to Document

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