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Smart pH-Sensitive Nanogels for Enhancing Synergistic Anticancer Effects of Integrin αvβ3 Specific Apoptotic Peptide
Yurui Xu1, Lei Sun1, Shujun Feng1
1National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences , Nanjing University , Nanjing 210093 , China.
Abstract:
Apoptotic peptide (kla), which can trigger the mitochondria-mediated apoptotic programmed cell death, has been widely recognized as a potential anticancer agent. However, its therapeutic potential has been significantly impaired by its poor biostability, lack of tumor specificity, and particularly low cellular uptake. Herein, a linear peptide Arg-Trp-d-Arg-Asn-Arg (RWrNR) was identified as an integrin αvβ3 specific ligand with a nanomolar dissociation constant (Kd = 0.95 nM), which can greatly improve kla antitumor activity (IC50 = 8.81 μM) by improving its cellular uptake, compared to the classic integrin-recognition motif c-RGDyK (IC50 = 37.96 μM). Particularly, the RWrNR-kla conjugate can be entrapped in acidic sensitive nanogels (RK/Parg/CMCS-NGs), composed of poly-l-arginine (Parg) and carboxymethyl chitosan (CMCS, pI = 6.8), which can not only carry out controlled release of RWrNR-kla in response to the tumor acidic microenvironment, and consequently enhance its tumor specificity and cell internalization, but also trigger tumor-associated macrophages to generate nitric oxide, leading to enhanced synergistic anticancer efficacy. Importantly, RK/Parg/CMCS-NGs have been proven to effectively activate the apoptosis signaling pathway in vivo and significantly inhibit tumor growth with minimal adverse effects. To summarize, RK/Parg/CMCS-NGs are a promising apoptotic peptide-based therapeutics with enhanced tumor accumulation, cytosolic delivery, and synergistic anticancer effects, thereby holding great potential for the treatment of malignant tumors.
Insights
A novel nanogel formulation (RK/Parg/CMCS-NGs) enhances the anticancer efficacy of an apoptotic peptide (kla) by improving tumor targeting and cellular uptake. This targeted delivery system shows significant tumor growth inhibition with minimal side effects in vivo.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapeutics
Background:
- Apoptotic peptides show anticancer potential but suffer from poor biostability, tumor specificity, and cellular uptake.
- Integrin αvβ3 is a promising target for enhancing drug delivery to tumors.
- Acid-sensitive nanogels offer potential for controlled drug release in the tumor microenvironment.
Purpose of the Study:
- To develop a targeted drug delivery system to overcome the limitations of apoptotic peptides for cancer treatment.
- To enhance the anticancer efficacy and tumor specificity of the apoptotic peptide kla using a novel nanogel formulation.
- To investigate the in vivo therapeutic potential and safety of the developed nanocarrier system.
Main Methods:
- Identification of a linear peptide (RWrNR) specific for integrin αvβ3.
- Conjugation of RWrNR with kla and encapsulation into acidic-sensitive nanogels (RK/Parg/CMCS-NGs) composed of poly-l-arginine and carboxymethyl chitosan.
- In vitro and in vivo evaluation of cellular uptake, tumor targeting, controlled release, synergistic anticancer effects, and therapeutic efficacy.
Main Results:
- The RWrNR peptide exhibited high affinity for integrin αvβ3 (Kd = 0.95 nM), significantly improving kla's antitumor activity compared to c-RGDyK.
- RK/Parg/CMCS-NGs demonstrated pH-sensitive controlled release of RWrNR-kla, enhancing tumor specificity and cellular internalization.
- The nanogel formulation activated apoptosis signaling pathways in vivo, significantly inhibited tumor growth, and showed minimal adverse effects.
Conclusions:
- RK/Parg/CMCS-NGs represent a promising nanocarrier for apoptotic peptide-based cancer therapeutics.
- The formulation enhances tumor accumulation, cytosolic delivery, and synergistic anticancer effects, holding great potential for malignant tumor treatment.
- This approach offers a strategy to improve the therapeutic index of apoptotic peptides by addressing their delivery and specificity challenges.
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