دورية أكاديمية
Ultra-Long-Term Delivery of Hydrophilic Drugs Using Injectable In Situ Cross-Linked Depots.
| العنوان: | Ultra-Long-Term Delivery of Hydrophilic Drugs Using Injectable In Situ Cross-Linked Depots. |
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| المؤلفون: | Lee S; Harvard Medical School, Boston, MA, USA.; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA., Zhao S; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA., Jiang W; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14215, USA., Chen X; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA., Zhu L; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA., Joseph J; Harvard Medical School, Boston, MA, USA.; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA., Agus E; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA., Mary HB; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA., Barooj S; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA., Slaughter K; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA., Cheung K; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA., Luo JN; Harvard Medical School, Boston, MA, USA.; Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA., Shukla C; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA., Gao J; Harvard Medical School, Boston, MA, USA.; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA.; College of Engineering, University of Massachusetts Amherst, MA, USA., Lee D; Harvard Medical School, Boston, MA, USA.; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA., Balakrishnan B; Somaiya Centre for Integrated Science education and research, SKSC, Somaiya Vidyavihar University, Mumbai, 400077, India., Jiang C; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA., Gorantla A; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA., Woo S; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14215, USA., Karp JM; Harvard Medical School, Boston, MA, USA.; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Broad Institute, Cambridge, MA 02142, USA.; Harvard Stem Cell Institute, Cambridge, MA 02138, USA., Joshi N; Harvard Medical School, Boston, MA, USA.; Center for Accelerated Medical Innovation, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Aug 28. Date of Electronic Publication: 2024 Aug 28. |
| نوع المنشور: | Journal Article; Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Achieving ultra-long-term release of hydrophilic drugs over several months remains a significant challenge for existing long-acting injectables (LAIs). Existing platforms, such as in situ forming implants (ISFI), exhibit high burst release due to solvent efflux and microsphere-based approaches lead to rapid drug diffusion due to significant water exchange and large pores. Addressing these challenges, we have developed an injectable platform that, for the first time, achieves ultra-long-term release of hydrophilic drugs for over six months. This system employs a methacrylated ultra-low molecular weight pre-polymer (polycaprolactone) to create in situ cross-linked depots (ISCD). The ISCD's solvent-free design and dense mesh network, both attributed to the ultra-low molecular weight of the pre-polymer, effectively minimizes burst release and water influx/efflux. In vivo studies in rats demonstrate that ISCD outperforms ISFI by achieving lower burst release and prolonged drug release. We demonstrated the versatility of ISCD by showcasing ultra-long-term delivery of several hydrophilic drugs, including antiretrovirals (tenofovir alafenamide, emtricitabine, abacavir, and lamivudine), antibiotics (vancomycin and amoxicillin) and an opioid antagonist naltrexone. Additionally, ISCD achieved ultra-long-term release of the hydrophobic drug tacrolimus and enabled co-delivery of hydrophilic drug combinations encapsulated in a single depot. We also identified design parameters to tailor the polymer network, tuning drug release kinetics and ISCD degradation. Pharmacokinetic modeling predicted over six months of drug release in humans, significantly surpassing the one-month standard achievable for hydrophilic drugs with existing LAIs. The platform's biodegradability, retrievability, and biocompatibility further underscore its potential for improving treatment adherence in chronic conditions. Competing Interests: Competing interests S.L., S.Z, J.M.K. and N.J. have one pending patent based on the ISCD formulation described in this manuscript. J.M.K has been a paid consultant and or equity holder for companies (listed here: https://www.karplab.net/team/jeff-karp) including biotechnologies companies such as Stempeutics, Sanofi, Celltex, LifeVaultBio, Takeda, Ligandal, Camden Partners, Stemgent, Biogen, Pancryos, Element Biosciences, Frequency Therapeutics, Corner Therapeutics, Quthero, and Mesoblast. J.M.K. has been a paid consultant and or equity holder for multiple biotechnology companies. The interests of J.M.K. were reviewed and are subject to a management plan overseen by his institution in accordance with its conflict of interest policies. |
| معلومات مُعتمدة: | R21 DA057701 United States DA NIDA NIH HHS |
| تواريخ الأحداث: | Date Created: 20240910 Latest Revision: 20240916 |
| رمز التحديث: | 20240916 |
| مُعرف محوري في PubMed: | PMC11382995 |
| DOI: | 10.1101/2023.11.04.565631 |
| PMID: | 39253509 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2692-8205 |
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| DOI: | 10.1101/2023.11.04.565631 |