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Preparation and Characterization of Individual and Multi-drug Loaded Physically Entrapped Polymeric Micelles
Published on: August 28, 2015
Design, synthesis and biological evaluation of novel dimeric and tetrameric cRGD-paclitaxel conjugates for
A Bianchi1, D Arosio, P Perego
1Centro Interdipartimentale Studi Biomolecolari e Applicazioni Industriali, Università degli Studi di Milano, Via Fantoli 16/15, I-20138 Milano, Italy.
Abstract:
Integrins are associated with tumour cell survival and progression, and their expression has been shown to be increased in tumours. Thus, four novel conjugates of the tripeptide integrin ligand Arg-Gly-Asp (RGD) and the cytotoxic agent paclitaxel (cRGD-PTX) were prepared to investigate the potential of the multivalent presentation of the RGD moiety in improving the antitumor efficacy of PTX by tumour targeting. PTX was conjugated to two or four integrin recognizing ligands. The influence of multivalent presentation on in vitro αvβ3-receptor affinity was confirmed. For all the conjugates compared to the previously synthesized monovalent counterparts, an enhancement of the binding strength was observed; this behaviour was more pronounced when considering the tetravalent presented RGD-conjugate. Cell growth inhibition assays on a panel of human tumour cell lines showed remarkable cytotoxic activity for all conjugates with IC50 values in a nanomolar range. Among the four conjugates, the bivalent derivative 3b was selected for in vivo studies in an ovarian carcinoma cell model xenografted in immunodeficient mice. A marked antitumor activity was observed, similar to that of PTX, but with a much more favourable toxicity profile. Overall, the novel cRGD-PTX conjugates disclosed here represent promising candidates for further advancement in the domain of targeted anti-tumour therapy.
Insights
Novel Arg-Gly-Asp (RGD) and paclitaxel (PTX) conjugates show enhanced tumor targeting and efficacy. Multivalent RGD presentation improved PTX
Area of Science:
- Integrin-targeted drug delivery
- Anticancer therapeutics development
- Molecular conjugation chemistry
Background:
- Integrins are upregulated in tumors, mediating cell survival and progression.
- Paclitaxel (PTX) is a potent chemotherapeutic agent with broad-spectrum activity.
- Targeted delivery strategies are needed to enhance PTX efficacy and reduce toxicity.
Purpose of the Study:
- To synthesize and evaluate novel Arg-Gly-Asp (RGD)-paclitaxel (PTX) conjugates (cRGD-PTX).
- To investigate the impact of multivalent RGD presentation on tumor targeting and antitumor efficacy.
- To assess the in vitro and in vivo therapeutic potential of cRGD-PTX conjugates.
Main Methods:
- Synthesis of four novel PTX conjugates with varying numbers of RGD ligands (bivalent and tetravalent).
- In vitro assessment of αvβ3-receptor affinity and binding strength.
- Cell growth inhibition assays on human tumor cell lines and in vivo efficacy studies in ovarian carcinoma xenografts.
Main Results:
- All synthesized cRGD-PTX conjugates demonstrated enhanced binding affinity compared to monovalent counterparts.
- Remarkable in vitro cytotoxic activity was observed across multiple tumor cell lines (nanomolar IC50 values).
- The bivalent conjugate (3b) showed significant in vivo antitumor activity with a favorable toxicity profile in mice.
Conclusions:
- Multivalent presentation of RGD ligands enhances the tumor-targeting capability of PTX conjugates.
- Novel cRGD-PTX conjugates exhibit potent and targeted antitumor activity with reduced toxicity.
- These conjugates represent promising candidates for advanced targeted cancer therapy.
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