Aldoxorubicin

Aldoxorubicin (INNO-206) is a tumor-targeted doxorubicin conjugate in development by CytRx. Specifically, it is the (6-maleimidocaproyl) hydrazone of doxorubicin. Essentially, this chemical name describes doxorubicin attached to an acid sensitive linker (N-ε-maleimidocaproic acid hydrazide, or EMCH).

Aldoxorubicin
Identifiers
PubChem CID
ChemSpider
KEGG
ECHA InfoCard100.244.879
Chemical and physical data
FormulaC37H42N4O13
Molar mass750.758 g·mol−1
3D model (JSmol)

The proposed mechanism of action is as follows:

  1. After administration, aldoxorubicin rapidly binds endogenous circulating albumin through the EMCH linker.
  2. Circulating albumin preferentially accumulates in tumors, bypassing uptake by other non-specific sites including heart, bone marrow and gastrointestinal tract.
  3. Once albumin-bound aldoxorubicin reaches the tumor, the acidic environment of the tumor causes cleavage of the acid sensitive linker.
  4. Free doxorubicin is released at the site of the tumor.

Clinical trials

Five phase I trials for safety characterization have been completed. Several phase II and III trials are underway.

Phase II

As of January 2017, there are 6 phase II clinical trials in progress:

  1. Second-line therapy for patients with glioblastoma[1]
  2. Treatment of HIV-positive patients with Kaposi's sarcoma[2]
  3. Combination therapy of ifosfamide and aldoxorubicin for treatment of metastatic or locally advanced sarcoma[3]
  4. Comparison of aldoxorubicin to the gold-standard treatment, topotecan, for metastatic small cell lung cancer[4]
  5. Treatment of advanced or metastatic pancreatic ductal adenocarcinoma[5]
  6. Comparison of aldoxorubicin and doxorubicin for patients with metastatic or locally advanced carcinoma[6]

Phase III

A phase III trial for patients with relapsed soft tissue sarcoma comparing aldoxorubicin with several other chemotherapeutics is expected to complete in 2018.[7] In November 2016, CytRx announced that preliminary results had been positive.[8]

References
  1. https://clinicaltrials.gov/ct2/show/NCT02014844
  2. https://clinicaltrials.gov/ct2/show/NCT02029430
  3. https://clinicaltrials.gov/ct2/show/NCT02235701
  4. https://clinicaltrials.gov/ct2/show/NCT02200757
  5. https://clinicaltrials.gov/ct2/show/NCT01580397
  6. https://clinicaltrials.gov/ct2/show/NCT01514188
  7. https://clinicaltrials.gov/ct2/show/NCT02049905?
  8. http://www.streetinsider.com/Conference+Calls/CytRx+(CYTR)+Announces+Statistically+Significant+Data+from+Aldoxorubicin+Phase+3+in+rr+STS/12289769.html
  • Kratz, F; Azab, S; Zeisig, R; Fichtner, I; Warnecke, A (Jan 2013). "Evaluation of combination therapy schedules of doxorubicin and an acid-sensitive albumin-binding prodrug of doxorubicin in the MIA PaCa-2 pancreatic xenograft model". Int J Pharm. 441 (1–2): 499–506. doi:10.1016/j.ijpharm.2012.11.003. PMID 23149257.
  • Walker, L; Perkins, E; Kratz, F; Raucher, D (Oct 2012). "Cell penetrating peptides fused to a thermally targeted biopolymer drug carrier improve the delivery and antitumor efficacy of an acid-sensitive doxorubicin derivative". Int J Pharm. 436 (1–2): 825–32. doi:10.1016/j.ijpharm.2012.07.043. PMC 3465682. PMID 22850291.
  • Kratz, F; Warnecke, A (Dec 2012). "Finding the optimal balance: challenges of improving conventional cancer chemotherapy using suitable combinations with nano-sized drug delivery systems". J Control Release. 164 (2): 221–35. doi:10.1016/j.jconrel.2012.05.045. PMID 22705248.
  • Sanchez, E; Li, M; Wang, C; Nichols, CM; Li, J; Chen, H; Berenson, JR (Jul 2012). "Anti-myeloma effects of the novel anthracycline derivative INNO-206". Clin. Cancer Res. 18 (14): 3856–67. doi:10.1158/1078-0432.CCR-11-3130. PMID 22619306.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.