SN-38-Cyclodextrin Complexation and Its Influence on the Solubility, Stability, and In Vitro Anticancer Activity Against Ovarian Cancer

Vangara, Kiran Kumar; Ali, Hamed I.; Lu, Dai; Liu, Jingbo Louise; Kolluru, Srikanth; Palakurthi, Srinath

doi:10.1208/s12249-013-0068-5

Cited by 36 publications

(35 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…route. We administered the precursor irinotecan instead of its active metabolite because of poor water solubility, high side effects and instability of SN-38 at a physiological pH [15], factors that limit its clinical use. The therapeutic impact of the different treatments was evaluated by bioluminescence imaging.…”

Section: Resultsmentioning

confidence: 99%

Drug conjugation to hyaluronan widens therapeutic indications for ovarian cancer

et al. 2015

View full text Add to dashboard Cite

Management of ovarian cancer still requires improvements in therapeutic options. A drug delivery strategy was tested that allows specific targeting of tumor cells in combination with a controlled release of a cytotoxic molecule. To this aim, the efficacy of a loco-regional intraperitoneal treatment with a bioconjugate (ONCOFID-S) derived by chemical linking of SN-38, the active metabolite of irinotecan (CPT-11), to hyaluronan was assessed in a mouse model of ovarian carcinomatosis.In vitro, the bioconjugate selectively interacted with ovarian cancer cells through the CD44 receptor, disclosed a dose-dependent tumor growth inhibition efficacy comparable to that of free SN-38 drug, and inhibited Topoisomerase I function leading to apoptosis by a mechanism involving caspase-3 and -7 activation and PARP cleavage. In vivo, the intraperitoneal administration of ONCOFID-S in tumor-bearing mice did not induce inflammation, and evidenced an improved therapeutic efficacy compared with CPT-11.In conclusion, SN-38 conjugation to hyaluronan significantly improved the profile of in vivo tolerability and widened the field of application of irinotecan. Therefore, this approach can be envisaged as a promising therapeutic strategy for loco-regional treatment of ovarian cancer.

show abstract

Section: Resultsmentioning

confidence: 99%

Drug conjugation to hyaluronan widens therapeutic indications for ovarian cancer

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Attempts have been made to develop formulation approaches enabling parenteral administration of solubilized SN-38 in its chemically unmodified form. Complexation with cyclodextrins has recently been reported to dramatically increase solubility of SN-38 (from 0.08 μg to 50 μg per mL) [36]. However, despite these improvements, this value remains orders of magnitude lower than that achievable by applying chemical modifications to the parent molecule.…”

Section: Discussionmentioning

confidence: 99%

Nanoparticle-mediated delivery of a rapidly activatable prodrug of SN-38 for neuroblastoma therapy

et al. 2015

View full text Add to dashboard Cite

Nanomedicine-based strategies have the potential to improve therapeutic performance of a wide range of anticancer agents. However, the successful implementation of nanoparticulate delivery systems requires the development of adequately sized nanocarriers delivering their therapeutic cargo to the target in a protected, pharmacologically active form. The present studies focused on a novel nanocarrier-based formulation strategy for SN-38, a topoisomerase I inhibitor with proven anticancer potential, whose clinical application is compromised by toxicity, poor stability and incompatibility with conventional delivery vehicles. SN-38 encapsulated in biodegradable sub-100 nm sized nanoparticles (NP) in the form of its rapidly activatable prodrug derivative with tocopherol succinate potently inhibited the growth of neuroblastoma cells in a dose- and exposure time-dependent manner, exhibiting a delayed response pattern distinct from that of free SN-38. In a xenograft model of neuroblastoma, prodrug-loaded NP caused rapid regression of established large tumors, significantly delayed tumor regrowth after treatment cessation and markedly extended animal survival. The NP formulation strategy enabled by a reversible chemical modification of the drug molecule offers a viable means for SN-38 delivery achieving sustained intratumoral drug levels and contributing to the potency and extended duration of antitumor activity, both prerequisites for effective treatment of neuroblastoma and other cancers.

show abstract

“…Presence of sulfobutyl [36]. Aqueous solubility of SN38 was enhanced by~30 --1400 times by CD complexation.…”

Section: Cyclodextrin Complexesmentioning

confidence: 99%

Challenges in SN38 drug delivery: current success and future directions

Palakurthi

2015

Expert Opinion on Drug Delivery

Self Cite

View full text Add to dashboard Cite

The challenges in SN38 drug delivery may be overcome by two ways: ensuring multiple layers of protection against degradation and slow but sustained release of therapeutically effective drug concentrations. It may also be achieved by preparing a polymer-drug conjugate and further encapsulating the conjugate in suitable carrier system; tumor-targeted SN38 delivery by using immunoconjugates, enzyme-activated prodrug therapy and antibody-directed nanoparticle delivery. However, selection of a suitable ligand for tumor targeting and use of safe and biocompatible nanoparticle systems play an important role in realizing this goal.

show abstract

SN-38-Cyclodextrin Complexation and Its Influence on the Solubility, Stability, and In Vitro Anticancer Activity Against Ovarian Cancer

Cited by 36 publications

References 34 publications

Drug conjugation to hyaluronan widens therapeutic indications for ovarian cancer

Drug conjugation to hyaluronan widens therapeutic indications for ovarian cancer

Nanoparticle-mediated delivery of a rapidly activatable prodrug of SN-38 for neuroblastoma therapy

Challenges in SN38 drug delivery: current success and future directions

Contact Info

Product

Resources

About