To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner.

To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner.

To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner.

To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner.

To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner.

To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner.

To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner.

To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner.

To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner.

To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner.

To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner.

To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner.

To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner.

To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner.

To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner.

To address these challenges, we developed a novel peptide-drug conjugate (PDC) to target pan-KRAS mutant cancers by exploiting enhanced albumin metabolism in KRAS mutant cancer cells .Such enhanced albumin metabolism is particularly found in cancer cells with oncogenic hypermutations in the RAS-PI3K signaling pathway, which are associated with the proliferation and survival of cancer cells. Particularly, Ras hyperactivated cancer cells in various solid tumors use macropinocytosis as a nutrient scavenging source for intracellular uptake of extracellular proteins, including albumin. Recent studies evidenced that the Ras superfamily of small guanosine triphosphatases (GTPases) including Rac, Cdc42, Arf6, and Rab5 are known stimulating factors or receptors for promoting membrane ruffle formation via actin polymerization as well as vacuolization of macropinosome. However, this altered mechanism can be taken advantage of as a potential drug delivery route in targeting RAS-transformed cancer cells. For this study, we adopted a previously developed albumin-binding caspase-3-cleavable peptide-doxorubicin conjugate (MPD1). In contrast to cytostatic small molecule inhibitors, MPD1 uses a cytotoxic anti-cancer agent (doxorubicin) as its warhead to capitalize on its potency to directly kill cancer cells non-selectively. More specifically, the albumin-bound MPD1 is intended to be delivered into KRAS mutant cancer cells through enhanced macropinocytosis and subsequently degraded by lysosomal enzymes to release the cytotoxic payload, which can induce apoptosis within albumin-engulfing cancer cells. Furthermore, albumin metabolism-induced apoptotic cells release caspase-3 to activate unabsorbed extracellular albumin-bound MPD1 through the cleavage of DEVD peptide to free doxorubicin, which induces the subsequent apoptosis of neighboring cancer cells in a non-selective manner.